{"gene":"SDCBP","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":2008,"finding":"MDA-9/Syntenin physically interacts with c-Src via its PDZ domains, and this interaction promotes formation of an active FAK/c-Src signaling complex, leading to enhanced tumor cell invasion and metastatic spread in melanoma.","method":"Co-immunoprecipitation, antisense adenovirus knockdown, c-Src siRNA, in vivo metastasis model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic knockdown (antisense + siRNA), in vivo model, replicated across multiple papers (PMID:18832467, PMID:20228839, PMID:31406249)","pmids":["18832467"],"is_preprint":false},{"year":2010,"finding":"MDA-9/Syntenin-c-Src interactions are required for NF-κB activation; both PDZ domains (with PDZ2 dominant) are required. Deletion or point mutations of the PDZ binding motif preventing MDA-9/Syntenin association with c-Src reduce p38 MAPK and NF-κB activation, anchorage-independent growth, motility, and invasion.","method":"PDZ domain deletion/point mutation constructs, PP2 (Src inhibitor), siRNA, c-Src(-/-) knockout cell lines, NF-κB activation assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of PDZ domains, genetic KO, pharmacological inhibition, multiple orthogonal methods in one study","pmids":["20228839"],"is_preprint":false},{"year":2007,"finding":"MDA-9/Syntenin initiates a signaling cascade activating NF-κB through FAK and p38 MAPK in melanoma cells, promoting MT1-MMP expression and subsequent pro-MMP-2 activation to drive migration and ECM invasion. (NOTE: paper is retracted; confidence downgraded accordingly.)","method":"Antisense adenovirus, dominant-negative FAK (FRNK), IκBα super-repressor, invasion and migration assays","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 2 / Weak — paper is RETRACTED; findings may be unreliable despite multiple methods","pmids":["17308124"],"is_preprint":false},{"year":2010,"finding":"MDA-9/Syntenin mediates fibronectin (FN)-induced adhesion signaling by forming an interdependent regulatory loop with PKCα: MDA-9/Syntenin expression is required for FN-induced PKCα phosphorylation (Thr638/641), and PKCα activity is required for MDA-9/Syntenin expression; both are required for formation of integrin-β1/FAK/c-Src signaling complexes and downstream p38 MAPK, Cdc42, and NF-κB activation.","method":"PKCα inhibition, mda-9/syntenin siRNA knockdown, Co-IP of integrin-β1/FAK/c-Src complexes, phosphorylation assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal inhibition experiments, Co-IP, multiple downstream readouts, single lab but orthogonal methods","pmids":["20145126"],"is_preprint":false},{"year":2011,"finding":"MDA-9/Syntenin regulates Akt activation during adhesion to type I collagen by facilitating association of ILK with Akt and plasma membrane translocation of the ILK-Akt complex; it also facilitates assembly of integrin-β1/IPP (ILK-PINCH1-α-parvin) signaling complexes at the plasma membrane.","method":"Co-IP, plasma membrane fractionation, ILK mutant (E359K), mda-9/syntenin siRNA knockdown, fluorescence/confocal imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, subcellular fractionation, dominant-negative mutant, siRNA knockdown, multiple orthogonal methods in single study","pmids":["21828040"],"is_preprint":false},{"year":2011,"finding":"MDA-9/Syntenin binds ubiquitin non-covalently via a novel ubiquitin-binding motif (not previously described) identified by yeast two-hybrid; it is also itself ubiquitinated but is stable, suggesting ubiquitin interaction is not related to proteolysis. PDZ domain deletion inhibits filopodia formation.","method":"Yeast two-hybrid (modified ubiquitin K48R), non-covalent binding assays, PDZ-domain deletion constructs, filopodia imaging","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus domain deletion, single lab, limited orthogonal validation of ubiquitin binding in mammalian cells","pmids":["21359963"],"is_preprint":false},{"year":2012,"finding":"MDA-9/Syntenin induces tumor angiogenesis by interacting with the ECM to activate Src and FAK, leading to Akt phosphorylation, HIF-1α induction, and transcriptional activation of IGFBP-2; secreted IGFBP-2 promotes angiogenesis and stimulates endothelial cells to produce VEGF-A.","method":"Gain-of-function/loss-of-function genetics, tube formation assay, CAM assay, xenograft model, Co-IP/signaling pathway analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function genetics, multiple in vitro and in vivo assays, single lab","pmids":["23233738"],"is_preprint":false},{"year":2013,"finding":"MDA-9/Syntenin physically interacts with EGFR (co-localization confirmed in cell lines and primary UCC tumors) and regulates EGFR, AKT, PI3K, and c-Src expression/activation; overexpression alters EMT markers (β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, TCF4).","method":"Co-IP, immunofluorescence co-localization, gain-of-function/knockdown, logistic regression with tumor samples","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and co-localization, in vitro and in vivo, single lab","pmids":["23873690"],"is_preprint":false},{"year":2016,"finding":"MDA-9/Syntenin uses its PDZ1 domain to interact with TGFβ1; this interaction upregulates active RhoA and Cdc42 levels, driving EMT and invasion in breast cancer cells. Re-introduction of TGFβ1 in MDA-9-silenced cells restores RhoA/Cdc42 activity and partially rescues invasion.","method":"Co-IP (PDZ1 domain interaction with TGFβ1), RhoA/Cdc42 activity assays, MDA-9 silencing/overexpression, 2D/3D morphology, in vivo lung metastasis model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP mapping to PDZ1, rescue experiment, in vivo model, single lab","pmids":["27863394"],"is_preprint":false},{"year":2016,"finding":"MDA-9/Syntenin translocates to the nucleus upon EGF stimulation, uses its PDZ1 domain to bind Slug transcription factor, recruits HDAC1, and enhances Slug-mediated transcriptional repression, promoting EMT, cancer invasion, and metastasis in lung adenocarcinoma.","method":"Co-IP (PDZ1-Slug interaction), HDAC1 recruitment assay, nuclear translocation imaging, PDZ domain mutants, invasion/metastasis assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, domain mapping, nuclear localization experiments, multiple cell-based assays, single lab","pmids":["26561205"],"is_preprint":false},{"year":2016,"finding":"In the tumor microenvironment, host MDA-9/Syntenin expression modulates IL-17A expression and recruitment of myeloid-derived suppressor cells (MDSCs) and Th17 cells; knockout of mda-9/syntenin in host mice suppressed subcutaneous tumor growth and lung metastasis and delayed tumor initiation in a spontaneous melanoma GEM model.","method":"Mda-9/syntenin global knockout mice, syngeneic B16 xenograft, IV B16 model, GEM model, immune cell profiling","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in multiple in vivo models, immune cell profiling, single lab","pmids":["27341128"],"is_preprint":false},{"year":2016,"finding":"MDA-9/Syntenin NMR-guided fragment-based drug design identified PDZ1i (113B7), which inhibits MDA-9/Syntenin binding to EGFRvIII; both genetic knockdown (shmda-9) and PDZ1i treatment reduced post-radiation invasion gains, FAK and EGFRvIII signaling, and MMP-2/MMP-9 secretion in GBM cells, with PDZ1i passing the blood-brain barrier and prolonging survival in vivo.","method":"NMR-guided fragment-based drug design, shRNA knockdown, pharmacological inhibition (PDZ1i), Co-IP of MDA-9–EGFRvIII, invasion assay, in vivo orthotopic GBM model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — NMR structure-guided drug design, Co-IP of specific binding, genetic and pharmacological parallel approaches, in vivo validation","pmids":["28011764"],"is_preprint":false},{"year":2018,"finding":"MDA-9/Syntenin maintains protective autophagy in glioma stem cells (GSCs) under anoikis conditions through FAK- and PKC-mediated phosphorylation of BCL2 and suppression of excessive autophagy markers (ATG5, LAMP1, LC3B) via EGFR signaling; loss of MDA-9 deregulates this mechanism, causing autophagic cell death.","method":"Gain-of-function/loss-of-function genetics (siRNA, shRNA), western blot for p-BCL2/p-EGFR/ATG5/LAMP1/LC3B, FAK/PKC inhibitors, anoikis assays in GSC sphere cultures","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological approaches, multiple autophagy markers, single lab","pmids":["29760085"],"is_preprint":false},{"year":2018,"finding":"MDA-9/Syntenin physically interacts with IGF-1R upon IGFBP2 stimulation, regulating downstream STAT3 phosphorylation, which enhances MMP2/MMP9 expression and prostate cancer invasion.","method":"Co-IP (MDA-9–IGF1R), STAT3 phosphorylation assays, CRISPR/Cas9 KO, loss-of-function/gain-of-function, in vitro invasion assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed interaction, CRISPR KO, multiple cell line/functional readouts, single lab with multiple orthogonal methods","pmids":["29572229"],"is_preprint":false},{"year":2018,"finding":"MDA-9/Syntenin upregulates PD-L1 expression by inducing STAT3 Tyr705 phosphorylation, leading to CD8+ T cell apoptosis in vitro and in vivo and immune evasion in triple-negative breast cancer.","method":"Western blot, flow cytometry, STAT3 inhibition, in vivo 4T1 tumor model with syntenin KD/overexpression","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological STAT3 inhibition confirms pathway, genetic KD, in vivo confirmation, single lab","pmids":["29845474"],"is_preprint":false},{"year":2019,"finding":"In glioma stem cells (GSCs), MDA-9 regulates stemness genes (Nanog, Oct4, Sox2) through STAT3 activation and controls GSC survival via the NOTCH1 pathway through phospho-Src and DLL1; activated NOTCH1 regulates C-Myc through RBPJK. Knockdown of MDA-9 simultaneously disrupts NOTCH1/C-Myc and p-STAT3/Nanog pathways, causing loss of stemness and apoptosis.","method":"siRNA/shRNA knockdown, pathway inhibitors, western blot for NOTCH1 cleavage/STAT3/Nanog/Oct4/Sox2, GSC sphere assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with multiple pathway readouts, epistasis analysis, single lab","pmids":["27472461"],"is_preprint":false},{"year":2019,"finding":"In prostate cancer stem cells (PCSCs), MDA-9-mediated multiple drug resistance, stemness, and survival are regulated through STAT3 activation; activated STAT3 controls chemoresistance via protective autophagy and MDR1 surface expression; the STAT3 and c-Myc pathways are interconnected downstream of MDA-9.","method":"Genetic loss-of-function (siRNA/shRNA), pharmacological inhibitors, western blot, flow cytometry for MDR1, autophagy assays, chemosensitivity assays (docetaxel, trichostatin-A)","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays, pharmacological and genetic approaches, single lab","pmids":["31878027"],"is_preprint":false},{"year":2019,"finding":"Blocking MDA-9/Syntenin by shRNA or the PDZ1i small-molecule inhibitor downregulates integrin α6 and β4, diminishes Src activity, suppresses Rho-Rac-Cdc42 activity, inhibits cofilin and MMPs, and reduces neuroblastoma migration and metastasis in vivo; overexpression of integrin α6/β4 rescues invasion, placing integrins upstream of Src in MDA-9-mediated migration.","method":"shRNA, siRNA, PDZ1i pharmacological inhibitor, integrin overexpression rescue, Rho/Rac/Cdc42 activity assays, in vivo metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological parallel approaches, rescue experiment establishing epistasis, in vivo validation, single lab","pmids":["31406249"],"is_preprint":false},{"year":2020,"finding":"AURKA binds to SDCBP and phosphorylates it at Ser131 and Thr200, inhibiting ubiquitination-mediated SDCBP degradation; phosphorylated SDCBP activates the EGFR-PI3K-Akt signaling pathway by binding to EGFR and preventing EGFR internalization, promoting ESCC tumor growth.","method":"Co-IP (AURKA–SDCBP), phosphorylation site mapping (Ser131/Thr200), ubiquitination assays, EGFR internalization assay, in vitro kinase assay, xenograft model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct phosphorylation with site identification, Co-IP, ubiquitination assay, EGFR trafficking assay, in vivo validation, multiple orthogonal methods","pmids":["32572158"],"is_preprint":false},{"year":2021,"finding":"MDA-9/Syntenin PDZ1 domain pharmacological inhibition (PDZ1i) suppresses breast cancer metastasis and deregulates myeloid-derived suppressor cell (MDSC) differentiation via the STAT3/IL-1β pathway, concomitantly promoting cytotoxic T lymphocyte activation.","method":"PDZ1i treatment, genetic silencing, lung metastasis model, MDSC differentiation assays, T cell activation assays, IL-1β pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic parallel, in vivo metastasis model, immune cell readouts, single lab","pmids":["34016751"],"is_preprint":false},{"year":2023,"finding":"SDCBP stabilizes YAP1 by directly interacting with the TAD domain of YAP1 (primarily via its PDZ1 domain) and inhibiting CK1δ/ε-mediated YAP1-S384/S387 phosphorylation, thereby suppressing β-TrCP-mediated ubiquitination and proteasomal degradation of YAP1, promoting PDAC proliferation and metastasis.","method":"Co-IP, pull-down assays, ubiquitination assays, domain mapping (PDZ1), phosphorylation site analysis, organoid models, KPC mouse model, PDX model","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP and pulldown with domain mapping, ubiquitination/phosphorylation mechanistic dissection, multiple in vivo models including KPC and PDX","pmids":["36828627"],"is_preprint":false},{"year":2023,"finding":"SDCBP via its PDZ1 domain disassembles the SCFFBXO22-BACH1 ubiquitin-ligase complex, preventing BACH1 K48-linked polyubiquitination and proteasomal degradation; SDCBP knockdown degrades BACH1, downregulates BACH1-induced metastatic genes, and upregulates BACH1-repressed ETC genes (NDUFA4, COX6B2), increasing mitochondrial activity.","method":"Co-IP (SDCBP–BACH1–FBXO22 complex disassembly), ubiquitination assays (K48-linked), PDZ1 domain-specific knockdown constructs, gene expression analysis, mitochondrial activity assays, in vivo TNBC tumor model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP of trimeric complex, K48-ubiquitination assay, domain mapping, functional metabolic readouts, in vivo model, multiple orthogonal methods","pmids":["40263598"],"is_preprint":false},{"year":2023,"finding":"IVMT-Rx-3 (PDZ1i joined to PDZ2-binding peptide TNYYFV via PEG linker) simultaneously blocks both PDZ domains of MDA-9/Syntenin, inhibiting its interaction with Src, reducing NF-κB activation and MMP-2/MMP-9 expression, and repressing melanoma metastasis in vivo; combined with immune checkpoint inhibitor, antimetastatic effects are enhanced.","method":"NMR/fragment-based drug design, dual-PDZ inhibitor synthesis, Src Co-IP, NF-κB assay, MMP expression, in vivo melanoma metastasis model, combination with checkpoint inhibitor","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — structure-guided design with NMR, biochemical co-IP validation of mechanism, in vivo efficacy model","pmids":["37721536"],"is_preprint":false},{"year":2023,"finding":"Crystal structure of MDA-9/Syntenin PDZ1 domain in complex with small-molecule inhibitor PI1B was solved; mutagenesis of PDZ domain residues validated the protein-ligand interaction modes; PI1A and PI2A (PDZ1/PDZ2 inhibitors) blocked natural substrate binding (fluorescence polarization) and suppressed MDA-MB-231 breast cancer cell migration.","method":"X-ray crystallography (PDZ1–PI1B complex), NMR (transferred paramagnetic relaxation enhancement), site-directed mutagenesis, competitive fluorescence polarization, cell migration assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis validation and competitive binding assay in one study","pmids":["36834839"],"is_preprint":false},{"year":2023,"finding":"In the bone metastasis niche, tumor cell-derived PDGF-AA induces CXCL5 expression in bone marrow-derived mesenchymal stromal cells (BM-MSCs) by suppressing MDA-9-dependent YAP/MST signaling; CXCL5 drives tumor cell proliferation and immune suppression. MDA-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases.","method":"MDA-9 knockout tumor cells, conditioned media experiments, signaling assays (YAP/MST), in vivo bone metastasis models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, pathway signaling evidence, in vivo bone metastasis model, single lab","pmids":["37922327"],"is_preprint":false},{"year":2014,"finding":"MDA-9/Syntenin is dramatically upregulated by rFVIIa/FX combination in melanoma cells and physically interacts with c-Src through its PDZ binding motif following TF·FVIIa·Xa stimulation; this signaling involves PAR-1/c-Src/Rho GTPases Rac1 and Cdc42/JNK axis, activating paxillin, NF-κB, and MMP-2, and is required for TF·FVIIa·Xa-induced migration, invasion, and metastasis.","method":"Co-IP (MDA-9–c-Src), PDZ motif mutants, Rho GTPase activity assays, siRNA knockdown, invasion/migration assays, in vivo metastasis model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with PDZ mutants, multiple downstream pathway readouts, in vivo model, single lab","pmids":["25505176"],"is_preprint":false},{"year":2013,"finding":"In glioblastoma cells, MDA-9/Syntenin overexpression increases activation of c-Src, p38 MAPK, and NF-κB, leading to elevated MMP-2 expression and IL-8 secretion; knockdown inhibits invasion, migration, and anchorage-independent growth and reduces tumor size and invasion in orthotopic xenografts.","method":"Gain-of-function/loss-of-function (overexpression/shRNA), western blot signaling analysis, Matrigel invasion, soft agar, orthotopic xenograft","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — parallel gain/loss-of-function, multiple in vitro assays, in vivo orthotopic model, single lab","pmids":["24305713"],"is_preprint":false},{"year":2012,"finding":"MDA-9/Syntenin promotes brain glioma cell migration by activating FAK-JNK and FAK-AKT signaling downstream of fibronectin adhesion; phosphorylation of FAK at Tyr397, Tyr576, and Tyr925 (but not Tyr861) is increased, and inhibition of JNK (SP600125) or PI3K (LY294002) decreases migration.","method":"Stable overexpression in glioma cells, wound-healing migration assay, western blot phosphorylation mapping, specific kinase inhibitors","journal":"Asian Pacific journal of cancer prevention","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment, pharmacological inhibition without rescue or genetic controls, single lab","pmids":["22938480"],"is_preprint":false},{"year":2016,"finding":"MDA-9/Syntenin interacts with the PDZ1 domain binding partner SPRR1B to disrupt differentiation signaling, and co-localizes with VEGFR1 to alter angiogenesis in HNSCC; silencing MDA-9 induced squamous differentiation and reduced VEGFR1 expression in vitro and in vivo.","method":"PDZ1 interaction mapping (SPRR1B), VEGFR1 co-localization (immunofluorescence), siRNA knockdown, in vitro differentiation/angiogenesis assays, in vivo tumor model","journal":"Oncoscience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-localization and PDZ1 interaction without rigorous Co-IP, single lab, limited mechanistic dissection","pmids":["25593999"],"is_preprint":false},{"year":2012,"finding":"MDA-9/Syntenin inhibition in uveal melanoma cells suppresses FAK, AKT, and Src activation and reduces HGF-triggered Matrigel invasion and wound-healing migration; overexpression has opposite effects, placing MDA-9 upstream of FAK/AKT/Src in uveal melanoma.","method":"siRNA knockdown, overexpression, Matrigel invasion, wound-healing assay, western blot for FAK/AKT/Src phosphorylation","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — parallel gain/loss-of-function, pathway readouts, but no direct binding assay or domain mapping; replicated for FAK/Src findings across labs","pmids":["22267972"],"is_preprint":false},{"year":2017,"finding":"Wild-type SDCBP interacts with c-Src (Co-IP confirmed) and promotes phosphorylation of c-Src at Tyr419; this interaction requires the PDZ domain (SDCBP lacking the PDZ domain has no effect on c-Src phosphorylation); dasatinib blocks this phosphorylation and SDCBP-induced cell cycle (G1/S) progression.","method":"Co-immunoprecipitation, PDZ-domain deletion constructs, dasatinib pharmacological inhibition, cell cycle analysis, xenograft model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain deletion, pharmacological confirmation, in vivo tumor formation, single lab","pmids":["28141839"],"is_preprint":false},{"year":2025,"finding":"SDCBP knockdown inhibited HNSCC cancer stem cell markers, sensitized cells to cisplatin, and reduced Src activation (identified as the main downstream target of SDCBP), with reduced tumor growth and metastasis in vivo.","method":"SDCBP siRNA/shRNA depletion, Src activation assay, in vitro cisplatin sensitivity, in vivo xenograft model","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Src identified as key downstream target but only by western blot, no direct binding assay","pmids":["34638436"],"is_preprint":false},{"year":2025,"finding":"SDCBP promotes gastric cancer EMT via the ERK signaling pathway; knockdown of SDCBP or ERK signaling inhibition delayed cancer progression in xenograft experiments; SDCBP-knockdown in cancer cells also inhibited M2 polarization, reduced chemotaxis, and enhanced phagocytosis of co-cultured macrophages.","method":"SDCBP siRNA knockdown, ERK inhibitor, co-culture macrophage assays, xenograft model, western blot","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect pathway evidence, no direct binding assay, single lab","pmids":["40256939"],"is_preprint":false},{"year":2025,"finding":"SDCBP inhibition by IVMT-Rx-4 (improved PDZ1i derivative) suppresses PDGF-AA secretion from tumor cells and inhibits downstream signaling in BM-MSCs, blocking prostate cancer bone metastasis; combination with docetaxel enhanced survival in bone metastasis animal models.","method":"Small molecule (IVMT-Rx-4) pharmacological inhibition, PDGF-AA measurement, BM-MSC signaling assays, in vivo bone metastasis model, combination treatment","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pharmacological inhibition linked to specific secreted factor, in vivo combination model, single lab","pmids":["41865851"],"is_preprint":false}],"current_model":"SDCBP/MDA-9/Syntenin is a tandem PDZ-domain scaffold protein that acts as a master organizer of pro-invasive and pro-metastatic signaling complexes: its PDZ domains directly recruit c-Src to FAK, activate NF-κB via p38 MAPK, engage EGFRvIII/EGFR to prevent receptor internalization and drive PI3K-Akt signaling, stabilize YAP1 and BACH1 from proteasomal degradation, facilitate ILK-Akt plasma-membrane targeting, interact with TGFβ1/RhoA/Cdc42 to promote EMT, and upregulate PD-L1 via STAT3 to suppress anti-tumor immunity; additionally, AURKA phosphorylates SDCBP at Ser131/Thr200 to protect it from ubiquitin-mediated degradation, and structure-guided PDZ1 inhibitors have been developed that block these protein–protein interactions to suppress metastasis across multiple cancer types."},"narrative":{"mechanistic_narrative":"SDCBP/MDA-9/Syntenin is a tandem PDZ-domain scaffold that nucleates pro-invasive and pro-metastatic signaling complexes downstream of cell-matrix and growth-factor cues [PMID:18832467, PMID:21828040]. Its central mechanism is the PDZ-dependent recruitment of c-Src into an active FAK/c-Src module that drives p38 MAPK and NF-κB activation, anchorage-independent growth, motility, and invasion; both PDZ domains contribute, with PDZ2 dominant for NF-κB and the PDZ binding motif required for the c-Src association [PMID:18832467, PMID:20228839, PMID:28141839]. SDCBP couples integrin/fibronectin and collagen adhesion to this output, operating in a reciprocal loop with PKCα to assemble integrin-β1/FAK/c-Src complexes and facilitating plasma-membrane targeting of the ILK-PINCH1-α-parvin and ILK-Akt machinery [PMID:20145126, PMID:21828040]. Through its PDZ1 domain it engages EGFR/EGFRvIII to prevent receptor internalization and sustain PI3K-Akt signaling, an interaction reinforced when AURKA binds and phosphorylates SDCBP at Ser131/Thr200 to block its ubiquitin-mediated degradation [PMID:28011764, PMID:32572158]. SDCBP also acts as a stabilizing scaffold for oncogenic transcriptional regulators, binding the YAP1 TAD via PDZ1 to suppress CK1δ/ε phosphorylation and β-TrCP-mediated degradation, and disassembling the SCF^FBXO22-BACH1 complex to prevent BACH1 K48-linked polyubiquitination, thereby controlling metastatic gene programs and mitochondrial ETC gene expression [PMID:36828627, PMID:40263598]. It promotes EMT and STAT3-driven programs, including PD-L1 upregulation and immune evasion, and modulates the tumor microenvironment via myeloid-derived suppressor cell recruitment [PMID:29572229, PMID:29845474, PMID:40263598]. Structure-guided NMR and crystallographic studies of the PDZ1 domain enabled small-molecule (PDZ1i, IVMT-Rx series) and dual-PDZ inhibitors that block the Src, EGFRvIII, and downstream interactions to suppress metastasis across multiple cancers [PMID:28011764, PMID:37721536, PMID:36834839].","teleology":[{"year":2008,"claim":"Established the founding mechanism by showing SDCBP physically recruits c-Src through its PDZ domains to assemble an active FAK/c-Src complex driving melanoma invasion and metastasis.","evidence":"Reciprocal Co-IP, antisense adenovirus and c-Src siRNA knockdown, in vivo metastasis model","pmids":["18832467"],"confidence":"High","gaps":["Did not map which PDZ domain residues mediate c-Src binding","Downstream effectors of the FAK/c-Src complex not yet defined"]},{"year":2010,"claim":"Defined the signaling output of the SDCBP-c-Src interaction by establishing that both PDZ domains (PDZ2 dominant) are required to activate p38 MAPK and NF-κB and to support invasive phenotypes.","evidence":"PDZ domain deletion/point mutants, PP2, c-Src(-/-) cells, NF-κB assays","pmids":["20228839"],"confidence":"High","gaps":["Mechanism linking c-Src to p38 MAPK not fully resolved","Direct transcriptional targets of NF-κB not enumerated"]},{"year":2010,"claim":"Connected SDCBP to matrix adhesion by showing it forms a reciprocal regulatory loop with PKCα to assemble integrin-β1/FAK/c-Src complexes on fibronectin.","evidence":"PKCα inhibition, siRNA knockdown, Co-IP of integrin-β1/FAK/c-Src, phosphorylation assays","pmids":["20145126"],"confidence":"High","gaps":["Direct PKCα-SDCBP physical interaction not demonstrated","How SDCBP expression is controlled by PKCα activity unknown"]},{"year":2011,"claim":"Extended the adhesion scaffolding role by showing SDCBP facilitates ILK-Akt and integrin-β1/IPP complex assembly and plasma-membrane translocation during collagen adhesion.","evidence":"Co-IP, plasma membrane fractionation, ILK E359K mutant, siRNA, confocal imaging","pmids":["21828040"],"confidence":"High","gaps":["Whether SDCBP binds ILK directly or via an adaptor not resolved","PDZ-domain dependence of ILK-Akt targeting not mapped"]},{"year":2011,"claim":"Identified a novel non-covalent ubiquitin-binding capability and showed SDCBP is itself ubiquitinated yet stable, hinting at non-proteolytic ubiquitin functions.","evidence":"Yeast two-hybrid (K48R ubiquitin), non-covalent binding assays, PDZ deletion, filopodia imaging","pmids":["21359963"],"confidence":"Medium","gaps":["Ubiquitin binding not validated in mammalian cells","Functional consequence of SDCBP ubiquitination undefined"]},{"year":2013,"claim":"Linked SDCBP to receptor tyrosine kinase signaling by demonstrating EGFR co-localization and regulation of EGFR/PI3K/AKT/c-Src and EMT markers.","evidence":"Co-IP, immunofluorescence, gain/knockdown, tumor sample logistic regression","pmids":["23873690"],"confidence":"Medium","gaps":["Direct binding interface with EGFR not mapped","Causal ordering of EGFR vs Src activation not established here"]},{"year":2016,"claim":"Mapped specific PDZ1-domain interactions driving EMT, including TGFβ1 binding that elevates RhoA/Cdc42 and nuclear Slug-HDAC1 transcriptional repression upon EGF stimulation.","evidence":"Co-IP PDZ1 mapping, RhoA/Cdc42 activity assays, nuclear translocation imaging, rescue, in vivo metastasis","pmids":["27863394","26561205"],"confidence":"Medium","gaps":["Trigger for SDCBP nuclear translocation incompletely defined","Relative contribution of cytoplasmic vs nuclear SDCBP to EMT unresolved"]},{"year":2016,"claim":"Demonstrated a host/microenvironmental role by showing host SDCBP modulates IL-17A, MDSC and Th17 recruitment, with knockout suppressing tumor growth and metastasis.","evidence":"Global knockout mice, syngeneic and IV B16 models, GEM melanoma model, immune profiling","pmids":["27341128"],"confidence":"Medium","gaps":["Cell-intrinsic SDCBP signaling in host immune cells not dissected","Molecular link from SDCBP to IL-17A not defined"]},{"year":2016,"claim":"Achieved druggability by using NMR fragment-based design to create PDZ1i, which blocks SDCBP-EGFRvIII binding and post-radiation invasion in GBM and crosses the blood-brain barrier.","evidence":"NMR-guided design, shRNA, PDZ1i inhibition, Co-IP of SDCBP-EGFRvIII, orthotopic GBM model","pmids":["28011764"],"confidence":"High","gaps":["Off-target PDZ interactions of the inhibitor not fully characterized","PDZ2-mediated functions not addressed by PDZ1i alone"]},{"year":2018,"claim":"Expanded SDCBP into STAT3-axis biology by showing it binds IGF-1R to activate STAT3-MMP signaling and drives STAT3-Tyr705-dependent PD-L1 upregulation and CD8+ T cell apoptosis.","evidence":"Co-IP, CRISPR KO, STAT3 phosphorylation/inhibition assays, in vivo 4T1 model, flow cytometry","pmids":["29572229","29845474"],"confidence":"High","gaps":["Whether STAT3 activation is direct or Src/JAK-relayed not clarified","Generality of PD-L1 mechanism beyond TNBC untested"]},{"year":2018,"claim":"Implicated SDCBP in cancer stem cell survival and protective autophagy through FAK/PKC-BCL2 phosphorylation and STAT3/NOTCH1 stemness programs.","evidence":"siRNA/shRNA, kinase inhibitors, autophagy marker westerns, GSC sphere and anoikis assays","pmids":["29760085","27472461"],"confidence":"Medium","gaps":["Direct binding partners in the autophagy axis not identified","Single-lab evidence for stemness regulation"]},{"year":2019,"claim":"Placed integrins upstream of Src in SDCBP-driven migration and confirmed PDZ1i efficacy in neuroblastoma metastasis.","evidence":"shRNA, PDZ1i, integrin α6/β4 overexpression rescue, Rho/Rac/Cdc42 assays, in vivo metastasis","pmids":["31406249"],"confidence":"Medium","gaps":["Mechanism by which SDCBP regulates integrin levels unclear","Direct SDCBP-integrin physical interaction not shown"]},{"year":2020,"claim":"Revealed post-translational control of SDCBP by showing AURKA phosphorylates it at Ser131/Thr200 to block its ubiquitin-mediated degradation, enabling EGFR-PI3K-Akt activation via blocked EGFR internalization.","evidence":"Co-IP, phospho-site mapping, in vitro kinase assay, ubiquitination and EGFR internalization assays, xenograft","pmids":["32572158"],"confidence":"High","gaps":["Identity of the SDCBP E3 ligase not determined","How phosphorylation alters PDZ-EGFR engagement not structurally resolved"]},{"year":2023,"claim":"Established SDCBP as a stabilizing scaffold for oncogenic transcription factors by showing PDZ1-dependent stabilization of YAP1 (via CK1δ/ε and β-TrCP inhibition) and disassembly of the SCF-FBXO22-BACH1 ubiquitin-ligase complex.","evidence":"Co-IP, pull-down, K48-ubiquitination assays, domain mapping, organoid/KPC/PDX and TNBC in vivo models","pmids":["36828627","40263598"],"confidence":"High","gaps":["How a single PDZ1 surface accommodates structurally diverse clients unresolved","Whether YAP1 and BACH1 stabilization are competing or coordinate functions unknown"]},{"year":2023,"claim":"Advanced therapeutic targeting with dual-PDZ inhibitors and the first crystal structure of the PDZ1-inhibitor complex, validating structure-guided blockade of SDCBP protein-protein interactions.","evidence":"NMR/X-ray crystallography (PDZ1-PI1B), dual-PDZ inhibitor (IVMT-Rx-3), Src Co-IP, fluorescence polarization, in vivo melanoma metastasis with checkpoint combination","pmids":["37721536","36834839"],"confidence":"High","gaps":["Selectivity across the broader PDZ-domain proteome not fully profiled","Clinical translatability of dual-PDZ inhibitors untested"]},{"year":2023,"claim":"Connected SDCBP to the bone metastatic niche by showing tumor SDCBP supports PDGF-AA secretion that reprograms BM-MSCs via YAP/MST signaling toward immunosuppressive CXCL5.","evidence":"SDCBP knockout tumor cells, conditioned media, YAP/MST signaling assays, in vivo bone metastasis","pmids":["37922327"],"confidence":"Medium","gaps":["Mechanism linking SDCBP to PDGF-AA expression not defined","Single-lab niche model"]},{"year":null,"claim":"How SDCBP's PDZ1 surface selects among its many degradation-regulating clients (YAP1, BACH1, EGFR) and how phosphorylation reprograms this client repertoire remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of multi-client PDZ1 binding","E3 ligases controlling SDCBP turnover unidentified","Physiological (non-cancer) function of SDCBP not addressed in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4,30]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,20,21]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[20,21]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,18]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,30]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,11,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[18,20,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,14,19]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,4]}],"complexes":["FAK/c-Src signaling complex","integrin-β1/ILK-PINCH1-α-parvin (IPP) complex","SCF(FBXO22)-BACH1 ubiquitin-ligase complex (disassembled by SDCBP)"],"partners":["SRC","EGFR","YAP1","BACH1","AURKA","ILK","IGF1R","TGFB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00560","full_name":"Syntenin-1","aliases":["Melanoma differentiation-associated protein 9","MDA-9","Pro-TGF-alpha cytoplasmic domain-interacting protein 18","TACIP18","Scaffold protein Pbp1","Syndecan-binding protein 1"],"length_aa":298,"mass_kda":32.4,"function":"Multifunctional adapter protein involved in diverse array of functions including trafficking of transmembrane proteins, neuro and immunomodulation, exosome biogenesis, and tumorigenesis (PubMed:26291527). Positively regulates TGFB1-mediated SMAD2/3 activation and TGFB1-induced epithelial-to-mesenchymal transition (EMT) and cell migration in various cell types. May increase TGFB1 signaling by enhancing cell-surface expression of TGFR1 by preventing the interaction between TGFR1 and CAV1 and subsequent CAV1-dependent internalization and degradation of TGFR1 (PubMed:25893292). In concert with SDC1/4 and PDCD6IP, regulates exosome biogenesis (PubMed:22660413). Regulates migration, growth, proliferation, and cell cycle progression in a variety of cancer types (PubMed:26539120). In adherens junctions may function to couple syndecans to cytoskeletal proteins or signaling components. Seems to couple transcription factor SOX4 to the IL-5 receptor (IL5RA) (PubMed:11498591). May also play a role in vesicular trafficking (PubMed:11179419). Seems to be required for the targeting of TGFA to the cell surface in the early secretory pathway (PubMed:10230395)","subcellular_location":"Cell junction, focal adhesion; Cell junction, adherens junction; Cell membrane; Endoplasmic reticulum membrane; Nucleus; Melanosome; Cytoplasm, cytosol; Cytoplasm, cytoskeleton; Secreted, extracellular exosome; Membrane raft","url":"https://www.uniprot.org/uniprotkb/O00560/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SDCBP","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SDCBP","total_profiled":1310},"omim":[{"mim_id":"617358","title":"SYNDECAN-BINDING PROTEIN 2; SDCBP2","url":"https://www.omim.org/entry/617358"},{"mim_id":"602217","title":"SYNDECAN-BINDING PROTEIN; SDCBP","url":"https://www.omim.org/entry/602217"},{"mim_id":"270800","title":"SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE; SPG5A","url":"https://www.omim.org/entry/270800"},{"mim_id":"184430","title":"SRY-BOX 4; SOX4","url":"https://www.omim.org/entry/184430"},{"mim_id":"147851","title":"INTERLEUKIN 5 RECEPTOR, ALPHA; IL5RA","url":"https://www.omim.org/entry/147851"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SDCBP"},"hgnc":{"alias_symbol":["SYCL","MDA-9","SDCBP1"],"prev_symbol":[]},"alphafold":{"accession":"O00560","domains":[{"cath_id":"2.30.42.10","chopping":"110-190","consensus_level":"high","plddt":94.7684,"start":110,"end":190},{"cath_id":"2.30.42.10","chopping":"196-289","consensus_level":"high","plddt":95.2369,"start":196,"end":289}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00560","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00560-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00560-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SDCBP","jax_strain_url":"https://www.jax.org/strain/search?query=SDCBP"},"sequence":{"accession":"O00560","fasta_url":"https://rest.uniprot.org/uniprotkb/O00560.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00560/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00560"}},"corpus_meta":[{"pmid":"29760085","id":"PMC_29760085","title":"MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29760085","citation_count":110,"is_preprint":false},{"pmid":"16322237","id":"PMC_16322237","title":"mda-9/Syntenin: a positive regulator of melanoma metastasis.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16322237","citation_count":98,"is_preprint":false},{"pmid":"18832467","id":"PMC_18832467","title":"mda-9/Syntenin promotes metastasis in human melanoma cells by activating c-Src.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18832467","citation_count":96,"is_preprint":false},{"pmid":"28011764","id":"PMC_28011764","title":"Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28011764","citation_count":85,"is_preprint":false},{"pmid":"9511750","id":"PMC_9511750","title":"Melanoma differentiation associated gene-9, mda-9, is a human gamma interferon responsive gene.","date":"1998","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9511750","citation_count":80,"is_preprint":false},{"pmid":"23233738","id":"PMC_23233738","title":"MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23233738","citation_count":79,"is_preprint":false},{"pmid":"17308124","id":"PMC_17308124","title":"RETRACTED: mda-9/Syntenin regulates the metastatic phenotype in human melanoma cells by activating nuclear factor-kappaB.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17308124","citation_count":77,"is_preprint":false},{"pmid":"20145126","id":"PMC_20145126","title":"Activation of the integrin effector kinase focal adhesion kinase in cancer cells is regulated by crosstalk between protein kinase Calpha and the PDZ adapter protein mda-9/Syntenin.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20145126","citation_count":74,"is_preprint":false},{"pmid":"22267972","id":"PMC_22267972","title":"Mda-9/syntenin is expressed in uveal melanoma and correlates with metastatic progression.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22267972","citation_count":72,"is_preprint":false},{"pmid":"20228839","id":"PMC_20228839","title":"Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-kappaB.","date":"2010","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/20228839","citation_count":63,"is_preprint":false},{"pmid":"18451132","id":"PMC_18451132","title":"mda-9/Syntenin: more than just a simple adapter protein when it comes to cancer metastasis.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18451132","citation_count":62,"is_preprint":false},{"pmid":"22201728","id":"PMC_22201728","title":"MDA-9/syntenin: a positive gatekeeper of melanoma metastasis.","date":"2012","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/22201728","citation_count":62,"is_preprint":false},{"pmid":"23066033","id":"PMC_23066033","title":"Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23066033","citation_count":56,"is_preprint":false},{"pmid":"23873690","id":"PMC_23873690","title":"Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling.","date":"2013","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/23873690","citation_count":55,"is_preprint":false},{"pmid":"24305713","id":"PMC_24305713","title":"MDA-9/syntenin is a key regulator of glioma pathogenesis.","date":"2013","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24305713","citation_count":54,"is_preprint":false},{"pmid":"15518882","id":"PMC_15518882","title":"mda-9/syntenin: recent insights into a novel cell signaling and metastasis-associated gene.","date":"2004","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/15518882","citation_count":53,"is_preprint":false},{"pmid":"25219541","id":"PMC_25219541","title":"Targeting tumor invasion: the roles of MDA-9/Syntenin.","date":"2014","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/25219541","citation_count":50,"is_preprint":false},{"pmid":"23533663","id":"PMC_23533663","title":"Syndecan binding protein (SDCBP) is overexpressed in estrogen receptor negative breast cancers, and is a potential promoter for tumor proliferation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23533663","citation_count":46,"is_preprint":false},{"pmid":"29572229","id":"PMC_29572229","title":"The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29572229","citation_count":46,"is_preprint":false},{"pmid":"27720715","id":"PMC_27720715","title":"miR-216b suppresses breast cancer growth and metastasis by targeting SDCBP.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27720715","citation_count":45,"is_preprint":false},{"pmid":"32061839","id":"PMC_32061839","title":"MDA-9/Syntenin (SDCBP): Novel gene and therapeutic target for cancer metastasis.","date":"2020","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/32061839","citation_count":44,"is_preprint":false},{"pmid":"27863394","id":"PMC_27863394","title":"MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor β1 to enhance epithelial-mesenchymal transition in breast cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27863394","citation_count":44,"is_preprint":false},{"pmid":"25480418","id":"PMC_25480418","title":"MDA-9 and GRP78 as potential diagnostic biomarkers for early detection of melanoma metastasis.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25480418","citation_count":44,"is_preprint":false},{"pmid":"31947814","id":"PMC_31947814","title":"The MGF360-16R ORF of African Swine Fever Virus Strain Georgia Encodes for a Nonessential Gene That Interacts with Host Proteins SERTAD3 and SDCBP.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31947814","citation_count":41,"is_preprint":false},{"pmid":"32572158","id":"PMC_32572158","title":"SDCBP/MDA-9/syntenin phosphorylation by AURKA promotes esophageal squamous cell carcinoma progression through the EGFR-PI3K-Akt signaling pathway.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32572158","citation_count":40,"is_preprint":false},{"pmid":"36828627","id":"PMC_36828627","title":"SDCBP promotes pancreatic cancer progression by preventing YAP1 from β-TrCP-mediated proteasomal degradation.","date":"2023","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/36828627","citation_count":37,"is_preprint":false},{"pmid":"32410111","id":"PMC_32410111","title":"MDA-9/Syntenin/SDCBP: new insights into a unique multifunctional scaffold protein.","date":"2020","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/32410111","citation_count":37,"is_preprint":false},{"pmid":"29845474","id":"PMC_29845474","title":"Syntenin1/MDA-9 (SDCBP) induces immune evasion in triple-negative breast cancer by upregulating PD-L1.","date":"2018","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/29845474","citation_count":37,"is_preprint":false},{"pmid":"30118375","id":"PMC_30118375","title":"Regulation of protective autophagy in anoikis-resistant glioma stem cells by SDCBP/MDA-9/Syntenin.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30118375","citation_count":35,"is_preprint":false},{"pmid":"31878027","id":"PMC_31878027","title":"MDA-9/Syntenin (SDCBP) Is a Critical Regulator of Chemoresistance, Survival and Stemness in Prostate Cancer Stem Cells.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31878027","citation_count":34,"is_preprint":false},{"pmid":"28141839","id":"PMC_28141839","title":"Dasatinib inhibits c-src phosphorylation and prevents the proliferation of Triple-Negative Breast Cancer (TNBC) cells which overexpress Syndecan-Binding Protein (SDCBP).","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28141839","citation_count":33,"is_preprint":false},{"pmid":"31406249","id":"PMC_31406249","title":"Regulation of neuroblastoma migration, invasion, and in vivo metastasis by genetic and pharmacological manipulation of MDA-9/Syntenin.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31406249","citation_count":31,"is_preprint":false},{"pmid":"34016751","id":"PMC_34016751","title":"Pharmacological inhibition of MDA-9/Syntenin blocks breast cancer metastasis through suppression of IL-1β.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34016751","citation_count":30,"is_preprint":false},{"pmid":"27802291","id":"PMC_27802291","title":"ACTB, CDKN1B, GAPDH, GRB2, RHOA and SDCBP Were Identified as Reference Genes in Neuroendocrine Lung Cancer via the nCounter Technology.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27802291","citation_count":30,"is_preprint":false},{"pmid":"27341128","id":"PMC_27341128","title":"Knockout of MDA-9/Syntenin (SDCBP) expression in the microenvironment dampens tumor-supporting inflammation and inhibits melanoma metastasis.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27341128","citation_count":29,"is_preprint":false},{"pmid":"31345950","id":"PMC_31345950","title":"Suppression of Prostate Cancer Pathogenesis Using an MDA-9/Syntenin (SDCBP) PDZ1 Small-Molecule Inhibitor.","date":"2019","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31345950","citation_count":27,"is_preprint":false},{"pmid":"30502089","id":"PMC_30502089","title":"MiRNA-139-3p inhibits the proliferation, invasion, and migration of human glioma cells by targeting MDA-9/syntenin.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30502089","citation_count":26,"is_preprint":false},{"pmid":"26561205","id":"PMC_26561205","title":"MDA-9/Syntenin-Slug transcriptional complex promote epithelial-mesenchymal transition and invasion/metastasis in lung adenocarcinoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26561205","citation_count":25,"is_preprint":false},{"pmid":"22938480","id":"PMC_22938480","title":"Mda-9/syntenin promotes human brain glioma migration through focal adhesion kinase (FAK)-JNK and FAK-AKT signaling.","date":"2012","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/22938480","citation_count":25,"is_preprint":false},{"pmid":"21828040","id":"PMC_21828040","title":"mda-9/Syntenin protein positively regulates the activation of Akt protein by facilitating integrin-linked kinase adaptor function during adhesion to type I collagen.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21828040","citation_count":25,"is_preprint":false},{"pmid":"27472461","id":"PMC_27472461","title":"Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27472461","citation_count":24,"is_preprint":false},{"pmid":"26093898","id":"PMC_26093898","title":"Examination of Epigenetic and other Molecular Factors Associated with mda-9/Syntenin Dysregulation in Cancer Through Integrated Analyses of Public Genomic Datasets.","date":"2015","source":"Advances in cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26093898","citation_count":24,"is_preprint":false},{"pmid":"35592331","id":"PMC_35592331","title":"PRKAR1A and SDCBP Serve as Potential Predictors of Heart Failure Following Acute Myocardial Infarction.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35592331","citation_count":23,"is_preprint":false},{"pmid":"31349898","id":"PMC_31349898","title":"MDA-9/Syntenin: An emerging global molecular target regulating cancer invasion and metastasis.","date":"2019","source":"Advances in cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31349898","citation_count":23,"is_preprint":false},{"pmid":"29118922","id":"PMC_29118922","title":"IL-6 increases SDCBP expression, cell proliferation, and cell invasion by activating JAK2/STAT3 in human glioma cells.","date":"2017","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/29118922","citation_count":23,"is_preprint":false},{"pmid":"31024042","id":"PMC_31024042","title":"Repression of miR-135b-5p promotes metastasis of early-stage breast cancer by regulating downstream target SDCBP.","date":"2019","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31024042","citation_count":23,"is_preprint":false},{"pmid":"25593999","id":"PMC_25593999","title":"MDA-9/Syntenin regulates differentiation and angiogenesis programs in head and neck squamous cell carcinoma.","date":"2014","source":"Oncoscience","url":"https://pubmed.ncbi.nlm.nih.gov/25593999","citation_count":23,"is_preprint":false},{"pmid":"26291527","id":"PMC_26291527","title":"MDA-9/Syntenin Control.","date":"2015","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26291527","citation_count":21,"is_preprint":false},{"pmid":"34137173","id":"PMC_34137173","title":"Single-cell RNA sequencing identify SDCBP in ACE2-positive bronchial epithelial cells negatively correlates with COVID-19 severity.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34137173","citation_count":20,"is_preprint":false},{"pmid":"36209503","id":"PMC_36209503","title":"SDCBP-AS1 destabilizes β-catenin by regulating ubiquitination and SUMOylation of hnRNP K to suppress gastric tumorigenicity and metastasis.","date":"2022","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/36209503","citation_count":19,"is_preprint":false},{"pmid":"21359963","id":"PMC_21359963","title":"MDA-9/syntenin interacts with ubiquitin via a novel ubiquitin-binding motif.","date":"2011","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21359963","citation_count":19,"is_preprint":false},{"pmid":"34638436","id":"PMC_34638436","title":"SDCBP Modulates Stemness and Chemoresistance in Head and Neck Squamous Cell Carcinoma through Src Activation.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34638436","citation_count":15,"is_preprint":false},{"pmid":"30681320","id":"PMC_30681320","title":"Rethinking Glioblastoma Therapy: MDA-9/Syntenin Targeted Small Molecule.","date":"2019","source":"ACS chemical neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30681320","citation_count":15,"is_preprint":false},{"pmid":"30766662","id":"PMC_30766662","title":"A PDZ Protein MDA-9/Syntenin: As a Target for Cancer Therapy.","date":"2019","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/30766662","citation_count":14,"is_preprint":false},{"pmid":"30589231","id":"PMC_30589231","title":"MicroRNA-23a inhibits melanoma cell proliferation, migration, and invasion in mice through a negative feedback regulation of sdcbp and the MAPK/ERK signaling pathway.","date":"2018","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/30589231","citation_count":13,"is_preprint":false},{"pmid":"33432665","id":"PMC_33432665","title":"Downregulation of SDCBP inhibits cell proliferation and induces apoptosis by regulating PI3K/AKT/mTOR pathway in gastric carcinoma.","date":"2021","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33432665","citation_count":12,"is_preprint":false},{"pmid":"23180153","id":"PMC_23180153","title":"Expression patterns of MDA-9/syntenin during development of the mouse embryo.","date":"2012","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/23180153","citation_count":12,"is_preprint":false},{"pmid":"37922327","id":"PMC_37922327","title":"MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37922327","citation_count":11,"is_preprint":false},{"pmid":"37721536","id":"PMC_37721536","title":"Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis.","date":"2023","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37721536","citation_count":9,"is_preprint":false},{"pmid":"36834839","id":"PMC_36834839","title":"Inhibitors against Two PDZ Domains of MDA-9 Suppressed Migration of Breast Cancer Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36834839","citation_count":8,"is_preprint":false},{"pmid":"30608040","id":"PMC_30608040","title":"Potential Therapeutic Applications of MDA-9/Syntenin-NF-κB-RKIP Loop in Human Liver Carcinoma.","date":"2018","source":"Current molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30608040","citation_count":8,"is_preprint":false},{"pmid":"38555398","id":"PMC_38555398","title":"SDCBP modulates tumor microenvironment, tumor progression and anti-PD1 efficacy in colorectal cancer.","date":"2024","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/38555398","citation_count":7,"is_preprint":false},{"pmid":"25505176","id":"PMC_25505176","title":"MDA-9/syntenin is essential for factor VIIa-induced signaling, migration, and metastasis in melanoma cells.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25505176","citation_count":7,"is_preprint":false},{"pmid":"38649770","id":"PMC_38649770","title":"Dexrazoxane inhibits the growth of esophageal squamous cell carcinoma by attenuating SDCBP/MDA-9/syntenin-mediated EGFR-PI3K-Akt pathway activation.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38649770","citation_count":5,"is_preprint":false},{"pmid":"39486220","id":"PMC_39486220","title":"Knockdown of SDCBP induces autophagy to promote cardiomyocyte growth and angiogenesis in hypoxia/reoxygenation model.","date":"2024","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/39486220","citation_count":5,"is_preprint":false},{"pmid":"39873429","id":"PMC_39873429","title":"Identification of multicohort-based predictive signature for NMIBC recurrence reveals SDCBP as a novel oncogene in bladder cancer.","date":"2025","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39873429","citation_count":5,"is_preprint":false},{"pmid":"39456220","id":"PMC_39456220","title":"Design and Synthesis of Small Molecule Probes of MDA-9/Syntenin.","date":"2024","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39456220","citation_count":4,"is_preprint":false},{"pmid":"40056146","id":"PMC_40056146","title":"MDA-9/Syntenin as a therapeutic cancer metastasis target: current molecular and preclinical understanding.","date":"2025","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/40056146","citation_count":4,"is_preprint":false},{"pmid":"36870688","id":"PMC_36870688","title":"Recurrent 8q11-13 Aberrations Leading to PLAG1 Rearrangements, Including Novel Chimeras HNRNPA2B1::PLAG1 and SDCBP::PLAG1, in Lipomatous Tumors.","date":"2023","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/36870688","citation_count":3,"is_preprint":false},{"pmid":"40263598","id":"PMC_40263598","title":"SDCBP/Syntenin-1 stabilizes BACH1 by disassembling the SCFFBXO22-BACH1 complex in triple-negative breast cancer.","date":"2025","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/40263598","citation_count":1,"is_preprint":false},{"pmid":"40256939","id":"PMC_40256939","title":"SDCBP Orchestrated Gastric Cancer Aggression Through Epithelial- Mesenchymal Transition and Macrophages M2 Polarization.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/40256939","citation_count":1,"is_preprint":false},{"pmid":"23245759","id":"PMC_23245759","title":"Molecular studies on chicken melanoma differentiation associated gene-9 (mda-9).","date":"2012","source":"Allergologia et immunopathologia","url":"https://pubmed.ncbi.nlm.nih.gov/23245759","citation_count":1,"is_preprint":false},{"pmid":"40634444","id":"PMC_40634444","title":"Anoikis-related biomarkers PARP1 and SDCBP as diagnostic and therapeutic targets for asthma.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40634444","citation_count":0,"is_preprint":false},{"pmid":"40571215","id":"PMC_40571215","title":"WISP3 upregulates SDCBP expression to promote the progression of non-small cell lung cancer via the TGF-β signaling pathway.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40571215","citation_count":0,"is_preprint":false},{"pmid":"41865851","id":"PMC_41865851","title":"MDA-9/Syntenin small molecule inhibitor IVMT-Rx-4 blocks prostate cancer bone metastasis.","date":"2026","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/41865851","citation_count":0,"is_preprint":false},{"pmid":"41423524","id":"PMC_41423524","title":"Decoding SDCBP's role in tumor progression and immune cells infiltration: from databases to macrophage validation.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41423524","citation_count":0,"is_preprint":false},{"pmid":"41033115","id":"PMC_41033115","title":"MDA-9/Syntenin promotes glioma cell proliferation and invasion via exosome-mediated activation of the PI3K-AKT signaling pathway.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41033115","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.08.652881","title":"Inhibitory TIGIT signalling is dependent on T cell receptor activation","date":"2025-05-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.08.652881","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41874,"output_tokens":8738,"usd":0.128346,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18684,"output_tokens":5626,"usd":0.117035,"stage2_stop_reason":"end_turn"},"total_usd":0.245381,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"MDA-9/Syntenin physically interacts with c-Src via its PDZ domains, and this interaction promotes formation of an active FAK/c-Src signaling complex, leading to enhanced tumor cell invasion and metastatic spread in melanoma.\",\n      \"method\": \"Co-immunoprecipitation, antisense adenovirus knockdown, c-Src siRNA, in vivo metastasis model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic knockdown (antisense + siRNA), in vivo model, replicated across multiple papers (PMID:18832467, PMID:20228839, PMID:31406249)\",\n      \"pmids\": [\"18832467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MDA-9/Syntenin-c-Src interactions are required for NF-κB activation; both PDZ domains (with PDZ2 dominant) are required. Deletion or point mutations of the PDZ binding motif preventing MDA-9/Syntenin association with c-Src reduce p38 MAPK and NF-κB activation, anchorage-independent growth, motility, and invasion.\",\n      \"method\": \"PDZ domain deletion/point mutation constructs, PP2 (Src inhibitor), siRNA, c-Src(-/-) knockout cell lines, NF-κB activation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of PDZ domains, genetic KO, pharmacological inhibition, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20228839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MDA-9/Syntenin initiates a signaling cascade activating NF-κB through FAK and p38 MAPK in melanoma cells, promoting MT1-MMP expression and subsequent pro-MMP-2 activation to drive migration and ECM invasion. (NOTE: paper is retracted; confidence downgraded accordingly.)\",\n      \"method\": \"Antisense adenovirus, dominant-negative FAK (FRNK), IκBα super-repressor, invasion and migration assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — paper is RETRACTED; findings may be unreliable despite multiple methods\",\n      \"pmids\": [\"17308124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MDA-9/Syntenin mediates fibronectin (FN)-induced adhesion signaling by forming an interdependent regulatory loop with PKCα: MDA-9/Syntenin expression is required for FN-induced PKCα phosphorylation (Thr638/641), and PKCα activity is required for MDA-9/Syntenin expression; both are required for formation of integrin-β1/FAK/c-Src signaling complexes and downstream p38 MAPK, Cdc42, and NF-κB activation.\",\n      \"method\": \"PKCα inhibition, mda-9/syntenin siRNA knockdown, Co-IP of integrin-β1/FAK/c-Src complexes, phosphorylation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal inhibition experiments, Co-IP, multiple downstream readouts, single lab but orthogonal methods\",\n      \"pmids\": [\"20145126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MDA-9/Syntenin regulates Akt activation during adhesion to type I collagen by facilitating association of ILK with Akt and plasma membrane translocation of the ILK-Akt complex; it also facilitates assembly of integrin-β1/IPP (ILK-PINCH1-α-parvin) signaling complexes at the plasma membrane.\",\n      \"method\": \"Co-IP, plasma membrane fractionation, ILK mutant (E359K), mda-9/syntenin siRNA knockdown, fluorescence/confocal imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, subcellular fractionation, dominant-negative mutant, siRNA knockdown, multiple orthogonal methods in single study\",\n      \"pmids\": [\"21828040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MDA-9/Syntenin binds ubiquitin non-covalently via a novel ubiquitin-binding motif (not previously described) identified by yeast two-hybrid; it is also itself ubiquitinated but is stable, suggesting ubiquitin interaction is not related to proteolysis. PDZ domain deletion inhibits filopodia formation.\",\n      \"method\": \"Yeast two-hybrid (modified ubiquitin K48R), non-covalent binding assays, PDZ-domain deletion constructs, filopodia imaging\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus domain deletion, single lab, limited orthogonal validation of ubiquitin binding in mammalian cells\",\n      \"pmids\": [\"21359963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MDA-9/Syntenin induces tumor angiogenesis by interacting with the ECM to activate Src and FAK, leading to Akt phosphorylation, HIF-1α induction, and transcriptional activation of IGFBP-2; secreted IGFBP-2 promotes angiogenesis and stimulates endothelial cells to produce VEGF-A.\",\n      \"method\": \"Gain-of-function/loss-of-function genetics, tube formation assay, CAM assay, xenograft model, Co-IP/signaling pathway analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function genetics, multiple in vitro and in vivo assays, single lab\",\n      \"pmids\": [\"23233738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MDA-9/Syntenin physically interacts with EGFR (co-localization confirmed in cell lines and primary UCC tumors) and regulates EGFR, AKT, PI3K, and c-Src expression/activation; overexpression alters EMT markers (β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, TCF4).\",\n      \"method\": \"Co-IP, immunofluorescence co-localization, gain-of-function/knockdown, logistic regression with tumor samples\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and co-localization, in vitro and in vivo, single lab\",\n      \"pmids\": [\"23873690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDA-9/Syntenin uses its PDZ1 domain to interact with TGFβ1; this interaction upregulates active RhoA and Cdc42 levels, driving EMT and invasion in breast cancer cells. Re-introduction of TGFβ1 in MDA-9-silenced cells restores RhoA/Cdc42 activity and partially rescues invasion.\",\n      \"method\": \"Co-IP (PDZ1 domain interaction with TGFβ1), RhoA/Cdc42 activity assays, MDA-9 silencing/overexpression, 2D/3D morphology, in vivo lung metastasis model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP mapping to PDZ1, rescue experiment, in vivo model, single lab\",\n      \"pmids\": [\"27863394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDA-9/Syntenin translocates to the nucleus upon EGF stimulation, uses its PDZ1 domain to bind Slug transcription factor, recruits HDAC1, and enhances Slug-mediated transcriptional repression, promoting EMT, cancer invasion, and metastasis in lung adenocarcinoma.\",\n      \"method\": \"Co-IP (PDZ1-Slug interaction), HDAC1 recruitment assay, nuclear translocation imaging, PDZ domain mutants, invasion/metastasis assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, domain mapping, nuclear localization experiments, multiple cell-based assays, single lab\",\n      \"pmids\": [\"26561205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In the tumor microenvironment, host MDA-9/Syntenin expression modulates IL-17A expression and recruitment of myeloid-derived suppressor cells (MDSCs) and Th17 cells; knockout of mda-9/syntenin in host mice suppressed subcutaneous tumor growth and lung metastasis and delayed tumor initiation in a spontaneous melanoma GEM model.\",\n      \"method\": \"Mda-9/syntenin global knockout mice, syngeneic B16 xenograft, IV B16 model, GEM model, immune cell profiling\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in multiple in vivo models, immune cell profiling, single lab\",\n      \"pmids\": [\"27341128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDA-9/Syntenin NMR-guided fragment-based drug design identified PDZ1i (113B7), which inhibits MDA-9/Syntenin binding to EGFRvIII; both genetic knockdown (shmda-9) and PDZ1i treatment reduced post-radiation invasion gains, FAK and EGFRvIII signaling, and MMP-2/MMP-9 secretion in GBM cells, with PDZ1i passing the blood-brain barrier and prolonging survival in vivo.\",\n      \"method\": \"NMR-guided fragment-based drug design, shRNA knockdown, pharmacological inhibition (PDZ1i), Co-IP of MDA-9–EGFRvIII, invasion assay, in vivo orthotopic GBM model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — NMR structure-guided drug design, Co-IP of specific binding, genetic and pharmacological parallel approaches, in vivo validation\",\n      \"pmids\": [\"28011764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MDA-9/Syntenin maintains protective autophagy in glioma stem cells (GSCs) under anoikis conditions through FAK- and PKC-mediated phosphorylation of BCL2 and suppression of excessive autophagy markers (ATG5, LAMP1, LC3B) via EGFR signaling; loss of MDA-9 deregulates this mechanism, causing autophagic cell death.\",\n      \"method\": \"Gain-of-function/loss-of-function genetics (siRNA, shRNA), western blot for p-BCL2/p-EGFR/ATG5/LAMP1/LC3B, FAK/PKC inhibitors, anoikis assays in GSC sphere cultures\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological approaches, multiple autophagy markers, single lab\",\n      \"pmids\": [\"29760085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MDA-9/Syntenin physically interacts with IGF-1R upon IGFBP2 stimulation, regulating downstream STAT3 phosphorylation, which enhances MMP2/MMP9 expression and prostate cancer invasion.\",\n      \"method\": \"Co-IP (MDA-9–IGF1R), STAT3 phosphorylation assays, CRISPR/Cas9 KO, loss-of-function/gain-of-function, in vitro invasion assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed interaction, CRISPR KO, multiple cell line/functional readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29572229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MDA-9/Syntenin upregulates PD-L1 expression by inducing STAT3 Tyr705 phosphorylation, leading to CD8+ T cell apoptosis in vitro and in vivo and immune evasion in triple-negative breast cancer.\",\n      \"method\": \"Western blot, flow cytometry, STAT3 inhibition, in vivo 4T1 tumor model with syntenin KD/overexpression\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological STAT3 inhibition confirms pathway, genetic KD, in vivo confirmation, single lab\",\n      \"pmids\": [\"29845474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In glioma stem cells (GSCs), MDA-9 regulates stemness genes (Nanog, Oct4, Sox2) through STAT3 activation and controls GSC survival via the NOTCH1 pathway through phospho-Src and DLL1; activated NOTCH1 regulates C-Myc through RBPJK. Knockdown of MDA-9 simultaneously disrupts NOTCH1/C-Myc and p-STAT3/Nanog pathways, causing loss of stemness and apoptosis.\",\n      \"method\": \"siRNA/shRNA knockdown, pathway inhibitors, western blot for NOTCH1 cleavage/STAT3/Nanog/Oct4/Sox2, GSC sphere assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with multiple pathway readouts, epistasis analysis, single lab\",\n      \"pmids\": [\"27472461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In prostate cancer stem cells (PCSCs), MDA-9-mediated multiple drug resistance, stemness, and survival are regulated through STAT3 activation; activated STAT3 controls chemoresistance via protective autophagy and MDR1 surface expression; the STAT3 and c-Myc pathways are interconnected downstream of MDA-9.\",\n      \"method\": \"Genetic loss-of-function (siRNA/shRNA), pharmacological inhibitors, western blot, flow cytometry for MDR1, autophagy assays, chemosensitivity assays (docetaxel, trichostatin-A)\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays, pharmacological and genetic approaches, single lab\",\n      \"pmids\": [\"31878027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Blocking MDA-9/Syntenin by shRNA or the PDZ1i small-molecule inhibitor downregulates integrin α6 and β4, diminishes Src activity, suppresses Rho-Rac-Cdc42 activity, inhibits cofilin and MMPs, and reduces neuroblastoma migration and metastasis in vivo; overexpression of integrin α6/β4 rescues invasion, placing integrins upstream of Src in MDA-9-mediated migration.\",\n      \"method\": \"shRNA, siRNA, PDZ1i pharmacological inhibitor, integrin overexpression rescue, Rho/Rac/Cdc42 activity assays, in vivo metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological parallel approaches, rescue experiment establishing epistasis, in vivo validation, single lab\",\n      \"pmids\": [\"31406249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AURKA binds to SDCBP and phosphorylates it at Ser131 and Thr200, inhibiting ubiquitination-mediated SDCBP degradation; phosphorylated SDCBP activates the EGFR-PI3K-Akt signaling pathway by binding to EGFR and preventing EGFR internalization, promoting ESCC tumor growth.\",\n      \"method\": \"Co-IP (AURKA–SDCBP), phosphorylation site mapping (Ser131/Thr200), ubiquitination assays, EGFR internalization assay, in vitro kinase assay, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct phosphorylation with site identification, Co-IP, ubiquitination assay, EGFR trafficking assay, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"32572158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MDA-9/Syntenin PDZ1 domain pharmacological inhibition (PDZ1i) suppresses breast cancer metastasis and deregulates myeloid-derived suppressor cell (MDSC) differentiation via the STAT3/IL-1β pathway, concomitantly promoting cytotoxic T lymphocyte activation.\",\n      \"method\": \"PDZ1i treatment, genetic silencing, lung metastasis model, MDSC differentiation assays, T cell activation assays, IL-1β pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic parallel, in vivo metastasis model, immune cell readouts, single lab\",\n      \"pmids\": [\"34016751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SDCBP stabilizes YAP1 by directly interacting with the TAD domain of YAP1 (primarily via its PDZ1 domain) and inhibiting CK1δ/ε-mediated YAP1-S384/S387 phosphorylation, thereby suppressing β-TrCP-mediated ubiquitination and proteasomal degradation of YAP1, promoting PDAC proliferation and metastasis.\",\n      \"method\": \"Co-IP, pull-down assays, ubiquitination assays, domain mapping (PDZ1), phosphorylation site analysis, organoid models, KPC mouse model, PDX model\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP and pulldown with domain mapping, ubiquitination/phosphorylation mechanistic dissection, multiple in vivo models including KPC and PDX\",\n      \"pmids\": [\"36828627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SDCBP via its PDZ1 domain disassembles the SCFFBXO22-BACH1 ubiquitin-ligase complex, preventing BACH1 K48-linked polyubiquitination and proteasomal degradation; SDCBP knockdown degrades BACH1, downregulates BACH1-induced metastatic genes, and upregulates BACH1-repressed ETC genes (NDUFA4, COX6B2), increasing mitochondrial activity.\",\n      \"method\": \"Co-IP (SDCBP–BACH1–FBXO22 complex disassembly), ubiquitination assays (K48-linked), PDZ1 domain-specific knockdown constructs, gene expression analysis, mitochondrial activity assays, in vivo TNBC tumor model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP of trimeric complex, K48-ubiquitination assay, domain mapping, functional metabolic readouts, in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"40263598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IVMT-Rx-3 (PDZ1i joined to PDZ2-binding peptide TNYYFV via PEG linker) simultaneously blocks both PDZ domains of MDA-9/Syntenin, inhibiting its interaction with Src, reducing NF-κB activation and MMP-2/MMP-9 expression, and repressing melanoma metastasis in vivo; combined with immune checkpoint inhibitor, antimetastatic effects are enhanced.\",\n      \"method\": \"NMR/fragment-based drug design, dual-PDZ inhibitor synthesis, Src Co-IP, NF-κB assay, MMP expression, in vivo melanoma metastasis model, combination with checkpoint inhibitor\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — structure-guided design with NMR, biochemical co-IP validation of mechanism, in vivo efficacy model\",\n      \"pmids\": [\"37721536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure of MDA-9/Syntenin PDZ1 domain in complex with small-molecule inhibitor PI1B was solved; mutagenesis of PDZ domain residues validated the protein-ligand interaction modes; PI1A and PI2A (PDZ1/PDZ2 inhibitors) blocked natural substrate binding (fluorescence polarization) and suppressed MDA-MB-231 breast cancer cell migration.\",\n      \"method\": \"X-ray crystallography (PDZ1–PI1B complex), NMR (transferred paramagnetic relaxation enhancement), site-directed mutagenesis, competitive fluorescence polarization, cell migration assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis validation and competitive binding assay in one study\",\n      \"pmids\": [\"36834839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the bone metastasis niche, tumor cell-derived PDGF-AA induces CXCL5 expression in bone marrow-derived mesenchymal stromal cells (BM-MSCs) by suppressing MDA-9-dependent YAP/MST signaling; CXCL5 drives tumor cell proliferation and immune suppression. MDA-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases.\",\n      \"method\": \"MDA-9 knockout tumor cells, conditioned media experiments, signaling assays (YAP/MST), in vivo bone metastasis models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, pathway signaling evidence, in vivo bone metastasis model, single lab\",\n      \"pmids\": [\"37922327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MDA-9/Syntenin is dramatically upregulated by rFVIIa/FX combination in melanoma cells and physically interacts with c-Src through its PDZ binding motif following TF·FVIIa·Xa stimulation; this signaling involves PAR-1/c-Src/Rho GTPases Rac1 and Cdc42/JNK axis, activating paxillin, NF-κB, and MMP-2, and is required for TF·FVIIa·Xa-induced migration, invasion, and metastasis.\",\n      \"method\": \"Co-IP (MDA-9–c-Src), PDZ motif mutants, Rho GTPase activity assays, siRNA knockdown, invasion/migration assays, in vivo metastasis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with PDZ mutants, multiple downstream pathway readouts, in vivo model, single lab\",\n      \"pmids\": [\"25505176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In glioblastoma cells, MDA-9/Syntenin overexpression increases activation of c-Src, p38 MAPK, and NF-κB, leading to elevated MMP-2 expression and IL-8 secretion; knockdown inhibits invasion, migration, and anchorage-independent growth and reduces tumor size and invasion in orthotopic xenografts.\",\n      \"method\": \"Gain-of-function/loss-of-function (overexpression/shRNA), western blot signaling analysis, Matrigel invasion, soft agar, orthotopic xenograft\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — parallel gain/loss-of-function, multiple in vitro assays, in vivo orthotopic model, single lab\",\n      \"pmids\": [\"24305713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MDA-9/Syntenin promotes brain glioma cell migration by activating FAK-JNK and FAK-AKT signaling downstream of fibronectin adhesion; phosphorylation of FAK at Tyr397, Tyr576, and Tyr925 (but not Tyr861) is increased, and inhibition of JNK (SP600125) or PI3K (LY294002) decreases migration.\",\n      \"method\": \"Stable overexpression in glioma cells, wound-healing migration assay, western blot phosphorylation mapping, specific kinase inhibitors\",\n      \"journal\": \"Asian Pacific journal of cancer prevention\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment, pharmacological inhibition without rescue or genetic controls, single lab\",\n      \"pmids\": [\"22938480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MDA-9/Syntenin interacts with the PDZ1 domain binding partner SPRR1B to disrupt differentiation signaling, and co-localizes with VEGFR1 to alter angiogenesis in HNSCC; silencing MDA-9 induced squamous differentiation and reduced VEGFR1 expression in vitro and in vivo.\",\n      \"method\": \"PDZ1 interaction mapping (SPRR1B), VEGFR1 co-localization (immunofluorescence), siRNA knockdown, in vitro differentiation/angiogenesis assays, in vivo tumor model\",\n      \"journal\": \"Oncoscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-localization and PDZ1 interaction without rigorous Co-IP, single lab, limited mechanistic dissection\",\n      \"pmids\": [\"25593999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MDA-9/Syntenin inhibition in uveal melanoma cells suppresses FAK, AKT, and Src activation and reduces HGF-triggered Matrigel invasion and wound-healing migration; overexpression has opposite effects, placing MDA-9 upstream of FAK/AKT/Src in uveal melanoma.\",\n      \"method\": \"siRNA knockdown, overexpression, Matrigel invasion, wound-healing assay, western blot for FAK/AKT/Src phosphorylation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — parallel gain/loss-of-function, pathway readouts, but no direct binding assay or domain mapping; replicated for FAK/Src findings across labs\",\n      \"pmids\": [\"22267972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wild-type SDCBP interacts with c-Src (Co-IP confirmed) and promotes phosphorylation of c-Src at Tyr419; this interaction requires the PDZ domain (SDCBP lacking the PDZ domain has no effect on c-Src phosphorylation); dasatinib blocks this phosphorylation and SDCBP-induced cell cycle (G1/S) progression.\",\n      \"method\": \"Co-immunoprecipitation, PDZ-domain deletion constructs, dasatinib pharmacological inhibition, cell cycle analysis, xenograft model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain deletion, pharmacological confirmation, in vivo tumor formation, single lab\",\n      \"pmids\": [\"28141839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SDCBP knockdown inhibited HNSCC cancer stem cell markers, sensitized cells to cisplatin, and reduced Src activation (identified as the main downstream target of SDCBP), with reduced tumor growth and metastasis in vivo.\",\n      \"method\": \"SDCBP siRNA/shRNA depletion, Src activation assay, in vitro cisplatin sensitivity, in vivo xenograft model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Src identified as key downstream target but only by western blot, no direct binding assay\",\n      \"pmids\": [\"34638436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SDCBP promotes gastric cancer EMT via the ERK signaling pathway; knockdown of SDCBP or ERK signaling inhibition delayed cancer progression in xenograft experiments; SDCBP-knockdown in cancer cells also inhibited M2 polarization, reduced chemotaxis, and enhanced phagocytosis of co-cultured macrophages.\",\n      \"method\": \"SDCBP siRNA knockdown, ERK inhibitor, co-culture macrophage assays, xenograft model, western blot\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect pathway evidence, no direct binding assay, single lab\",\n      \"pmids\": [\"40256939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SDCBP inhibition by IVMT-Rx-4 (improved PDZ1i derivative) suppresses PDGF-AA secretion from tumor cells and inhibits downstream signaling in BM-MSCs, blocking prostate cancer bone metastasis; combination with docetaxel enhanced survival in bone metastasis animal models.\",\n      \"method\": \"Small molecule (IVMT-Rx-4) pharmacological inhibition, PDGF-AA measurement, BM-MSC signaling assays, in vivo bone metastasis model, combination treatment\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pharmacological inhibition linked to specific secreted factor, in vivo combination model, single lab\",\n      \"pmids\": [\"41865851\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SDCBP/MDA-9/Syntenin is a tandem PDZ-domain scaffold protein that acts as a master organizer of pro-invasive and pro-metastatic signaling complexes: its PDZ domains directly recruit c-Src to FAK, activate NF-κB via p38 MAPK, engage EGFRvIII/EGFR to prevent receptor internalization and drive PI3K-Akt signaling, stabilize YAP1 and BACH1 from proteasomal degradation, facilitate ILK-Akt plasma-membrane targeting, interact with TGFβ1/RhoA/Cdc42 to promote EMT, and upregulate PD-L1 via STAT3 to suppress anti-tumor immunity; additionally, AURKA phosphorylates SDCBP at Ser131/Thr200 to protect it from ubiquitin-mediated degradation, and structure-guided PDZ1 inhibitors have been developed that block these protein–protein interactions to suppress metastasis across multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SDCBP/MDA-9/Syntenin is a tandem PDZ-domain scaffold that nucleates pro-invasive and pro-metastatic signaling complexes downstream of cell-matrix and growth-factor cues [#0, #4]. Its central mechanism is the PDZ-dependent recruitment of c-Src into an active FAK/c-Src module that drives p38 MAPK and NF-\\u03baB activation, anchorage-independent growth, motility, and invasion; both PDZ domains contribute, with PDZ2 dominant for NF-\\u03baB and the PDZ binding motif required for the c-Src association [#0, #1, #30]. SDCBP couples integrin/fibronectin and collagen adhesion to this output, operating in a reciprocal loop with PKC\\u03b1 to assemble integrin-\\u03b21/FAK/c-Src complexes and facilitating plasma-membrane targeting of the ILK-PINCH1-\\u03b1-parvin and ILK-Akt machinery [#3, #4]. Through its PDZ1 domain it engages EGFR/EGFRvIII to prevent receptor internalization and sustain PI3K-Akt signaling, an interaction reinforced when AURKA binds and phosphorylates SDCBP at Ser131/Thr200 to block its ubiquitin-mediated degradation [#11, #18]. SDCBP also acts as a stabilizing scaffold for oncogenic transcriptional regulators, binding the YAP1 TAD via PDZ1 to suppress CK1\\u03b4/\\u03b5 phosphorylation and \\u03b2-TrCP-mediated degradation, and disassembling the SCF^FBXO22-BACH1 complex to prevent BACH1 K48-linked polyubiquitination, thereby controlling metastatic gene programs and mitochondrial ETC gene expression [#20, #21]. It promotes EMT and STAT3-driven programs, including PD-L1 upregulation and immune evasion, and modulates the tumor microenvironment via myeloid-derived suppressor cell recruitment [#13, #14, #21]. Structure-guided NMR and crystallographic studies of the PDZ1 domain enabled small-molecule (PDZ1i, IVMT-Rx series) and dual-PDZ inhibitors that block the Src, EGFRvIII, and downstream interactions to suppress metastasis across multiple cancers [#11, #22, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established the founding mechanism by showing SDCBP physically recruits c-Src through its PDZ domains to assemble an active FAK/c-Src complex driving melanoma invasion and metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP, antisense adenovirus and c-Src siRNA knockdown, in vivo metastasis model\",\n      \"pmids\": [\"18832467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map which PDZ domain residues mediate c-Src binding\", \"Downstream effectors of the FAK/c-Src complex not yet defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the signaling output of the SDCBP-c-Src interaction by establishing that both PDZ domains (PDZ2 dominant) are required to activate p38 MAPK and NF-\\u03baB and to support invasive phenotypes.\",\n      \"evidence\": \"PDZ domain deletion/point mutants, PP2, c-Src(-/-) cells, NF-\\u03baB assays\",\n      \"pmids\": [\"20228839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking c-Src to p38 MAPK not fully resolved\", \"Direct transcriptional targets of NF-\\u03baB not enumerated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected SDCBP to matrix adhesion by showing it forms a reciprocal regulatory loop with PKC\\u03b1 to assemble integrin-\\u03b21/FAK/c-Src complexes on fibronectin.\",\n      \"evidence\": \"PKC\\u03b1 inhibition, siRNA knockdown, Co-IP of integrin-\\u03b21/FAK/c-Src, phosphorylation assays\",\n      \"pmids\": [\"20145126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PKC\\u03b1-SDCBP physical interaction not demonstrated\", \"How SDCBP expression is controlled by PKC\\u03b1 activity unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the adhesion scaffolding role by showing SDCBP facilitates ILK-Akt and integrin-\\u03b21/IPP complex assembly and plasma-membrane translocation during collagen adhesion.\",\n      \"evidence\": \"Co-IP, plasma membrane fractionation, ILK E359K mutant, siRNA, confocal imaging\",\n      \"pmids\": [\"21828040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SDCBP binds ILK directly or via an adaptor not resolved\", \"PDZ-domain dependence of ILK-Akt targeting not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a novel non-covalent ubiquitin-binding capability and showed SDCBP is itself ubiquitinated yet stable, hinting at non-proteolytic ubiquitin functions.\",\n      \"evidence\": \"Yeast two-hybrid (K48R ubiquitin), non-covalent binding assays, PDZ deletion, filopodia imaging\",\n      \"pmids\": [\"21359963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin binding not validated in mammalian cells\", \"Functional consequence of SDCBP ubiquitination undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked SDCBP to receptor tyrosine kinase signaling by demonstrating EGFR co-localization and regulation of EGFR/PI3K/AKT/c-Src and EMT markers.\",\n      \"evidence\": \"Co-IP, immunofluorescence, gain/knockdown, tumor sample logistic regression\",\n      \"pmids\": [\"23873690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface with EGFR not mapped\", \"Causal ordering of EGFR vs Src activation not established here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped specific PDZ1-domain interactions driving EMT, including TGF\\u03b21 binding that elevates RhoA/Cdc42 and nuclear Slug-HDAC1 transcriptional repression upon EGF stimulation.\",\n      \"evidence\": \"Co-IP PDZ1 mapping, RhoA/Cdc42 activity assays, nuclear translocation imaging, rescue, in vivo metastasis\",\n      \"pmids\": [\"27863394\", \"26561205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trigger for SDCBP nuclear translocation incompletely defined\", \"Relative contribution of cytoplasmic vs nuclear SDCBP to EMT unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a host/microenvironmental role by showing host SDCBP modulates IL-17A, MDSC and Th17 recruitment, with knockout suppressing tumor growth and metastasis.\",\n      \"evidence\": \"Global knockout mice, syngeneic and IV B16 models, GEM melanoma model, immune profiling\",\n      \"pmids\": [\"27341128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic SDCBP signaling in host immune cells not dissected\", \"Molecular link from SDCBP to IL-17A not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Achieved druggability by using NMR fragment-based design to create PDZ1i, which blocks SDCBP-EGFRvIII binding and post-radiation invasion in GBM and crosses the blood-brain barrier.\",\n      \"evidence\": \"NMR-guided design, shRNA, PDZ1i inhibition, Co-IP of SDCBP-EGFRvIII, orthotopic GBM model\",\n      \"pmids\": [\"28011764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Off-target PDZ interactions of the inhibitor not fully characterized\", \"PDZ2-mediated functions not addressed by PDZ1i alone\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded SDCBP into STAT3-axis biology by showing it binds IGF-1R to activate STAT3-MMP signaling and drives STAT3-Tyr705-dependent PD-L1 upregulation and CD8+ T cell apoptosis.\",\n      \"evidence\": \"Co-IP, CRISPR KO, STAT3 phosphorylation/inhibition assays, in vivo 4T1 model, flow cytometry\",\n      \"pmids\": [\"29572229\", \"29845474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3 activation is direct or Src/JAK-relayed not clarified\", \"Generality of PD-L1 mechanism beyond TNBC untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Implicated SDCBP in cancer stem cell survival and protective autophagy through FAK/PKC-BCL2 phosphorylation and STAT3/NOTCH1 stemness programs.\",\n      \"evidence\": \"siRNA/shRNA, kinase inhibitors, autophagy marker westerns, GSC sphere and anoikis assays\",\n      \"pmids\": [\"29760085\", \"27472461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partners in the autophagy axis not identified\", \"Single-lab evidence for stemness regulation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed integrins upstream of Src in SDCBP-driven migration and confirmed PDZ1i efficacy in neuroblastoma metastasis.\",\n      \"evidence\": \"shRNA, PDZ1i, integrin \\u03b16/\\u03b24 overexpression rescue, Rho/Rac/Cdc42 assays, in vivo metastasis\",\n      \"pmids\": [\"31406249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SDCBP regulates integrin levels unclear\", \"Direct SDCBP-integrin physical interaction not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed post-translational control of SDCBP by showing AURKA phosphorylates it at Ser131/Thr200 to block its ubiquitin-mediated degradation, enabling EGFR-PI3K-Akt activation via blocked EGFR internalization.\",\n      \"evidence\": \"Co-IP, phospho-site mapping, in vitro kinase assay, ubiquitination and EGFR internalization assays, xenograft\",\n      \"pmids\": [\"32572158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the SDCBP E3 ligase not determined\", \"How phosphorylation alters PDZ-EGFR engagement not structurally resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established SDCBP as a stabilizing scaffold for oncogenic transcription factors by showing PDZ1-dependent stabilization of YAP1 (via CK1\\u03b4/\\u03b5 and \\u03b2-TrCP inhibition) and disassembly of the SCF-FBXO22-BACH1 ubiquitin-ligase complex.\",\n      \"evidence\": \"Co-IP, pull-down, K48-ubiquitination assays, domain mapping, organoid/KPC/PDX and TNBC in vivo models\",\n      \"pmids\": [\"36828627\", \"40263598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single PDZ1 surface accommodates structurally diverse clients unresolved\", \"Whether YAP1 and BACH1 stabilization are competing or coordinate functions unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Advanced therapeutic targeting with dual-PDZ inhibitors and the first crystal structure of the PDZ1-inhibitor complex, validating structure-guided blockade of SDCBP protein-protein interactions.\",\n      \"evidence\": \"NMR/X-ray crystallography (PDZ1-PI1B), dual-PDZ inhibitor (IVMT-Rx-3), Src Co-IP, fluorescence polarization, in vivo melanoma metastasis with checkpoint combination\",\n      \"pmids\": [\"37721536\", \"36834839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity across the broader PDZ-domain proteome not fully profiled\", \"Clinical translatability of dual-PDZ inhibitors untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected SDCBP to the bone metastatic niche by showing tumor SDCBP supports PDGF-AA secretion that reprograms BM-MSCs via YAP/MST signaling toward immunosuppressive CXCL5.\",\n      \"evidence\": \"SDCBP knockout tumor cells, conditioned media, YAP/MST signaling assays, in vivo bone metastasis\",\n      \"pmids\": [\"37922327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking SDCBP to PDGF-AA expression not defined\", \"Single-lab niche model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SDCBP's PDZ1 surface selects among its many degradation-regulating clients (YAP1, BACH1, EGFR) and how phosphorylation reprograms this client repertoire remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of multi-client PDZ1 binding\", \"E3 ligases controlling SDCBP turnover unidentified\", \"Physiological (non-cancer) function of SDCBP not addressed in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4, 30]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 20, 21]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [20, 21]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 18]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 11, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [18, 20, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 14, 19]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"FAK/c-Src signaling complex\",\n      \"integrin-\\u03b21/ILK-PINCH1-\\u03b1-parvin (IPP) complex\",\n      \"SCF(FBXO22)-BACH1 ubiquitin-ligase complex (disassembled by SDCBP)\"\n    ],\n    \"partners\": [\n      \"SRC\",\n      \"EGFR\",\n      \"YAP1\",\n      \"BACH1\",\n      \"AURKA\",\n      \"ILK\",\n      \"IGF1R\",\n      \"TGFB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}