Affinage

SIPA1

Signal-induced proliferation-associated protein 1 · UniProt Q96FS4

Length
1042 aa
Mass
112.1 kDa
Annotated
2026-06-10
95 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIPA1 is a Rap1 GTPase-activating protein whose catalytic activity resides in an N-terminal GAP domain (amino acids 10–183) and which negatively regulates Rap1-GTP levels across diverse contexts including cell adhesion, immune cell trafficking, hematopoietic homeostasis, and cancer metastasis (PMID:9022283, PMID:10373454, PMID:16142231). By restraining Rap1 activation, SIPA1 controls β1-integrin- and ECM-mediated adhesion: its overexpression rounds cells and reduces fibronectin adhesion, and the GAP function is required for normal aquaporin-2 trafficking in renal collecting ducts and for spatial control of Rap1-GTP at the T cell immunological synapse (PMID:10373454, PMID:15196935, PMID:15081616). In T cells, SIPA1 acts redundantly with Rasa3 to keep Rap1 inactive; combined loss triggers spontaneous, LFA-1/talin1-dependent adhesion and impaired lymph node egress (PMID:37545505). Its GAP activity is spatially organized and modulated by protein partners—AF-6 recruits SIPA1 and Rap1-GTP to attachment sites, alpha-actinin localizes it at the synapse, and nuclear Brd4 enhances its GAP activity to balance cell cycle progression (PMID:12590145, PMID:15081616, PMID:15456879). Beyond the cytoplasm, nuclear SIPA1 functions as a transcription factor that binds a TGAGTCAB motif through a defined DNA-binding region and a nuclear localization region (residues 140–179), directly activating transcription of integrin β1, fibronectin 1, EPAS1/HIF-2α, and MYH9 to drive cancer cell adhesion, invasion, glycolytic reprogramming, and macrophage recruitment (PMID:37500797, PMID:24704834, PMID:33753200, PMID:35096814, PMID:35453742). SIPA1 levels functionally determine metastatic capacity and are controlled epigenetically by promoter methylation and post-translationally by a UCHL3–ITCH ubiquitin axis, in which UCHL3 removes K48-linked ubiquitin at K805 to stabilize SIPA1 while ITCH promotes its degradation (PMID:16142231, PMID:32193333, PMID:41412211). In bone marrow, SIPA1 limits BCR-ABL+ leukemic progenitor expansion and shapes the mesenchymal niche, and in cardiac fibroblasts after myocardial infarction it drives a noncanonical RasGRP2–Ras–JNK pathway, independent of Rap1, to produce CCL2/CCL7/GM-CSF and promote maladaptive inflammation (PMID:17047059, PMID:29514790, PMID:40567222).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 Medium

    Established that SIPA1 carries intrinsic GTPase-activating activity localized to its N-terminus, defining it as a catalytic GAP rather than a passive adaptor.

    Evidence In vitro GTPase stimulatory assay with GST-fusion N-terminal fragment and mutagenesis in E. coli

    PMID:9022283

    Open questions at the time
    • Preference for Rsr1 over Rap1 in vitro left the physiological substrate ambiguous
    • No cellular validation of substrate specificity
  2. 1999 Medium

    Showed SIPA1 negatively regulates Rap1 in cells, linking its GAP activity to control of ECM-mediated adhesion.

    Evidence Inducible and retroviral overexpression with adhesion assays in 293T, HeLa, and 32D cells

    PMID:10373454

    Open questions at the time
    • Gain-of-function only; endogenous loss-of-function not tested
    • Single lab
  3. 2003 High

    Defined how SIPA1 GAP activity is spatially targeted, showing AF-6 recruits both SIPA1 and Rap1-GTP to attachment sites to control integrin adhesion.

    Evidence Reciprocal Co-IP in 293T cells and thymocytes, in vitro binding with mutants, inducible adhesion assays

    PMID:12590145

    Open questions at the time
    • Internal PDZ-ligand motif only 'probable'
    • Structural basis of recruitment unresolved
  4. 2004 High

    Extended SIPA1's GAP function to physiological membrane trafficking and revealed a nuclear partner balancing its activity in the cell cycle.

    Evidence AQP2 pulldown, KO mouse trafficking assays, and Brd4 interaction by BiFC/MS with GAP and cell-cycle readouts

    PMID:15081616 PMID:15196935 PMID:15456879

    Open questions at the time
    • Mechanism by which Brd4 enhances GAP activity not resolved
    • alpha-actinin interaction (Y2H) lacks in vitro validation
  5. 2005 High

    Demonstrated SIPA1 dose- and polymorphism-dependently controls metastatic capacity, establishing it as a functional metastasis-efficiency gene.

    Evidence Spontaneous metastasis assays with ectopic expression and shRNA in mice, plus Rap-GAP assays of variants

    PMID:16142231

    Open questions at the time
    • Whether metastatic effect is cytoplasmic GAP or nuclear function was not separated
  6. 2008 Medium

    Placed SIPA1 in the hematopoietic/leukemic context, showing it limits BCR-ABL+ progenitor expansion and physically complexes with BCR-ABL P190.

    Evidence BCR-ABL CML mouse model with serial transplantation; Co-IP in COS-1 and primary lymphoblasts with migration assays

    PMID:17047059 PMID:18813851

    Open questions at the time
    • Functional consequence of the SIPA1–P190 complex on kinase signaling not established
    • Mechanism of SIPA1 downregulation by BCR-ABL unknown
  7. 2008 Medium

    Implicated SIPA1 in stem cell self-renewal via Rap1/Raf/MEK/ERK, broadening its role beyond adhesion.

    Evidence RNAi knockdown in human ESCs with pluripotency marker and signaling readouts

    PMID:18033671

    Open questions at the time
    • Single knockdown approach without rescue
    • Direct link between SIPA1 GAP activity and ERK pathway not dissected
  8. 2011 High

    Connected SIPA1 metastasis function to dual mechanisms—attenuating Rap1-mediated ECM adhesion and reducing nuclear Brd4 to lower ECM gene expression.

    Evidence Gain/loss-of-function in prostate cancer cells with in vivo metastasis, Rap1 activation, and Brd4 immunoblot

    PMID:21251160

    Open questions at the time
    • How SIPA1 alters nuclear Brd4 levels mechanistically unclear
  9. 2014 High

    Identified nuclear SIPA1 as a direct transcriptional activator, showing it binds the integrin β1 promoter to drive invasion signaling.

    Evidence Subcellular fractionation, ChIP/promoter binding, and siRNA knockdown with FAK/Akt/MMP9 readouts in MDA-MB-231 cells

    PMID:24704834

    Open questions at the time
    • DNA-binding motif and domain not yet defined at this stage
    • Relationship between nuclear and GAP functions unresolved
  10. 2018 High

    Defined a non-cell-autonomous role in the bone marrow niche, showing Sipa1-deficient stroma drives myeloid neoplasia yet also enables anti-CML immunity via Cxcl9/T-cell recruitment.

    Evidence Sipa1 KO mice, bone marrow transplantation, T-cell depletion, RNA-seq of stromal cells, migration/cytokine assays

    PMID:29500416 PMID:29514790

    Open questions at the time
    • Direct SIPA1 substrates/targets in MSCs not identified
    • How niche dysregulation initiates MDS/MPN mechanistically unclear
  11. 2020 Medium

    Expanded the nuclear transcriptional program of SIPA1 to metabolic reprogramming, stemness, and EMT, and identified promoter methylation as an upstream control.

    Evidence Overexpression/knockdown in breast cancer cells with metabolic flux, SMAD2/3 and EMT readouts, bisulfite sequencing and demethylation

    PMID:32193333 PMID:33296812 PMID:35096814

    Open questions at the time
    • Direct vs indirect transcriptional control of EPAS1/SMAD targets not all resolved
    • Single-lab studies for each phenotype
  12. 2021 Medium

    Mapped a nuclear localization region required for SIPA1's nuclear oncogenic functions and linked SIPA1 to MET-dependent barrier function in lung cancer.

    Evidence Deletion mutagenesis of NLR (140–179) with localization/drug-resistance readouts; SIPA1 knockdown with MET protein/transcript and barrier assays

    PMID:33753200 PMID:33917539

    Open questions at the time
    • Import receptor for the NLR not identified in this study
    • Mechanism of SIPA1 control over MET internalization indirect
  13. 2022 Medium

    Linked nuclear SIPA1 transcriptional activity to tumor immune microenvironment shaping through MYH9 and extracellular-vesicle-mediated macrophage recruitment.

    Evidence SIPA1 knockdown, EV isolation, myosin-9 immunoblot, macrophage migration in vitro/in vivo, blebbistatin treatment

    PMID:35453742

    Open questions at the time
    • Direct ChIP evidence for MYH9 promoter binding not shown
    • EV loading mechanism unresolved
  14. 2023 High

    Provided direct biochemical proof that SIPA1 is a sequence-specific transcription factor, defining its TGAGTCAB-recognizing DNA-binding region, FN1 target, and Importin β1-dependent nuclear import.

    Evidence EMSA motif mapping, ChIP, DBR deletion mutants, Importin β1 Co-IP, in vivo xenograft and scRNA-seq

    PMID:37500797

    Open questions at the time
    • Full genome-wide target repertoire not defined
    • Structural basis of motif recognition unknown
  15. 2023 High

    Established the in vivo redundancy of SIPA1 with Rasa3 as a Rap1 brake controlling lymphocyte trafficking and egress.

    Evidence Rasa3/Sipa1 double-KO mice with LFA-1 blockade, talin1 and Rap1 epistasis rescues, and intravital imaging

    PMID:37545505

    Open questions at the time
    • Relative contribution of SIPA1 alone versus Rasa3 not separated
    • Spatial regulation in T cells not resolved
  16. 2024 Medium

    Identified STAT3 phosphorylation as a shared downstream effector through which SIPA1 drives EMT in colorectal cancer and VEGF-mediated angiogenesis in retinal Müller cells.

    Evidence Gain/loss-of-function with STAT3 inhibitor epistasis and pSTAT3/EMT/VEGF readouts

    PMID:38312659 PMID:39130435

    Open questions at the time
    • Mechanism by which SIPA1 activates STAT3 phosphorylation not defined
    • Whether GAP or nuclear function drives STAT3 activation unclear
  17. 2025 High

    Defined the post-translational control of SIPA1 stability and a Rap1-independent signaling role, revealing a UCHL3–ITCH ubiquitin axis at K805 and a noncanonical RasGRP2–Ras–JNK inflammatory pathway in cardiac fibroblasts.

    Evidence K48-linkage ubiquitination assays with K805 mutagenesis and writer/eraser/regulator identification; cardiac-fibroblast-specific Sipa1 conditional KO with pathway dissection

    PMID:40567222 PMID:41412211

    Open questions at the time
    • How SIPA1 engages RasGRP2-Ras-JNK independently of its GAP activity is unresolved
    • Conditions selecting Rap1-dependent vs noncanonical signaling unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIPA1's two distinct activities—cytoplasmic Rap1-GAP and nuclear sequence-specific transcription factor—are coordinated, partitioned, and switched within a cell remains unresolved.
  • No structural model coupling the GAP domain to DNA-binding function
  • Signals that direct SIPA1 to nucleus vs cytoplasm only partly mapped (Importin β1, NLR)
  • Genome-wide direct target set incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 1
Partners
ACTNAFDNAQP2BCR-ABLBRD4KPNB1RAP1UCHL3

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 SIPA1 (Spa-1) N-terminal fragment (amino acids 10-183) is sufficient for Rap GAP activity; Spa-1 preferentially stimulates Rsr1 GTPase rather than Rap1 GTPase, distinguishing it from GAP3m which prefers Rap1. In vitro GTPase stimulatory assay using GST-fusion protein expressed in E. coli; mutational analysis of N-terminal fragment The international journal of biochemistry & cell biology Medium 9022283
1999 SIPA1 (SPA-1) acts as a Rap1 GAP that negatively regulates Rap1 activation; overexpression in HeLa cells induces cell rounding and reduced adhesion to fibronectin-coated dishes, while suppression of Rap1 activation inhibits cell adhesion induced by extracellular matrix and soluble factors. Transfection of SPA-1 in 293T and HeLa cells; tetracycline-inducible overexpression system; retroviral overexpression in 32D cells; cell adhesion assays The Journal of biological chemistry Medium 10373454
2003 SPA-1 binds to the PDZ domain of the cytoskeleton-anchoring protein AF-6 via a probable internal PDZ ligand motif within its GAP-related domain. AF-6 recruits both SPA-1 and Rap1GTP to cell attachment sites, and co-expression of AF-6 inhibits Rap1GTP levels and β1 integrin-mediated cell adhesion to fibronectin in SPA-1-expressing conditions. Co-immunoprecipitation in 293T cells and thymocytes; in vitro binding studies with truncated fragments and mutants; immunostaining; tetracycline-inducible HeLa cell adhesion assays The Journal of biological chemistry High 12590145
2004 Bromodomain protein Brd4 interacts with SIPA1 in the nucleus of living cells; Brd4 enhances the Rap GAP activity of SIPA1. Ectopic expression of either protein alone disrupts normal cell cycle progression, but co-expression of both restores it, indicating a functional balance is required for proper cell division. Immunopurification and mass spectrometry; bimolecular fluorescence complementation in living cells; GAP activity assay; cell cycle analysis Molecular and cellular biology High 15456879
2004 SIPA1 (SPA-1) directly binds to aquaporin-2 (AQP2) via its PDZ domain, co-localizes with AQP2 in renal collecting ducts, and regulates AQP2 trafficking to the apical membrane. A SIPA1 mutant lacking Rap1GAP activity and constitutively active Rap1V12 inhibit AQP2 trafficking; AQP2 trafficking is impaired in SIPA1-deficient mice. Biochemical pulldown/Co-immunoprecipitation; immunolocalization; functional trafficking assay with GAP-dead mutant and Rap1V12; SIPA1 knockout mice FEBS letters High 15196935
2004 SIPA1 is specifically recruited to the immunological synapse upon T cell antigen recognition, co-localizing with actin and alpha-actinin. SIPA1 interacts with the actin-bundling protein alpha-actinin (identified by yeast two-hybrid), suggesting it restrains Rap1GTP levels at the local TCR-signaling complex. Anti-SPA-1 antibody immunostaining and GFP-SPA-1 live imaging; yeast two-hybrid interaction screen; immunostaining co-localization at immunological synapse Immunology letters Medium 15081616
2005 A nonsynonymous amino acid polymorphism in Sipa1 affects its Rap-GAP function; ectopic Sipa1 expression increases spontaneous metastasis while knockdown reduces it, demonstrating that Sipa1 levels correlate with and functionally regulate metastatic capacity. Spontaneous metastasis assays in mice; ectopic expression and shRNA knockdown; biochemical Rap-GAP activity assessment of polymorphic variants Nature genetics High 16142231
2006 In SPA-1-deficient mice, BCR-ABL+ hematopoietic progenitor cells (HPCs) sustain higher levels of Lin-c-Kit+ leukemic progenitors than wild-type HPCs and can serially transfer CML. BCR-ABL causes partial downregulation of endogenous SPA-1 expression, and endogenous SPA-1 normally limits expansion/survival of BCR-ABL+ leukemic progenitors. CML mouse model with BCR-ABL-transduced wild-type and SPA-1-deficient HPCs; serial transplantation experiments; flow cytometry; RT-PCR for SPA-1 expression Cancer research High 17047059
2008 BCR-ABL P190 forms a protein-protein complex with SPA-1 in COS-1 cells and primary lymphoblastic leukemia cells. The interaction did not affect P190 tyrosine kinase activity or SPA-1 tyrosine phosphorylation, but P190 and SPA-1 co-localized to peripheral actin structures and SPA-1 expression decreased migration of leukemic lymphoblasts. Co-immunoprecipitation in COS-1 cells and primary P190 BCR/ABL transgenic mouse lymphoblasts; tyrosine kinase assay; immunofluorescence co-localization; migration assay International journal of molecular medicine Medium 18813851
2008 In human embryonic stem cells (hESCs), Spa-1 is expressed and maintains self-renewal; RNAi-mediated Spa-1 knockdown causes hESCs to differentiate into three germ layers even under undifferentiated conditions. This effect is mediated via Rap1/Raf/MEK/ERK signaling. RNA interference (pSUPER.retro.puro vector) in hESCs; immunocytochemistry for pluripotency markers; Western blot for signaling pathway components The International journal of developmental biology Medium 18033671
2011 SPA-1 expression in human prostate cancer cells (LNCaP) promotes lymph node metastasis without affecting primary tumor size. SPA-1 attenuates ECM-mediated Rap1 activation, reduces adhesion to collagens and fibronectin. SPA-1 also decreases nuclear Brd4 levels, reducing expression of ECM-related genes. Dominant-active Rap1V12 or shRNA knockdown of SIPA1 suppresses metastasis. SIPA1 transduction in LNCaP; shRNA knockdown in PC3; in vivo metastasis assay in SCID mice; Rap1 activation assay; immunoblot for Brd4 and ECM-related proteins; cell adhesion assays Cancer science High 21251160
2014 SIPA1 is primarily localized to the nucleus in highly invasive breast cancer cells (MDA-MB-231). Nuclear SIPA1 directly interacts with the integrin β1 promoter and activates its transcription, promoting cell adhesion and invasion. SIPA1 knockdown reduces FAK and Akt phosphorylation and MMP9 expression downstream of integrin β1. Subcellular fractionation; chromatin immunoprecipitation (ChIP) / promoter interaction assay; SIPA1 knockdown by siRNA; Western blot for FAK, Akt, MMP9; invasion and adhesion assays Oncogene High 24704834
2018 Sipa1 deficiency in mice causes phenotypic and functional alterations of BM mesenchymal stem and progenitor cells prior to initiation of myeloproliferative neoplasm (MPN), with dysregulation of Dicer1, Kitl, Angptl1, Cxcl12, and Thpo. The altered Sipa1-/- BM niche is sufficient to drive MDS/MPN upon transplantation of normal hematopoietic cells. Sipa1 knockout mouse model; bone marrow transplantation; flow cytometry; RNA sequencing of BM stromal cells Blood advances High 29514790
2018 Sipa1-/- mesenchymal stromal cells (MSCs) show enhanced activation and directed migration toward Bcr-Abl+ cells, preferentially produce Cxcl9, which recruits Sipa1-/- memory T cells with augmented chemotactic activity, thereby eradicating Bcr-Abl+ hematopoietic progenitors. The resistance to CML requires both T cells and nonhematopoietic cells. Sipa1 knockout mouse model; bone marrow transplantation; T cell depletion experiments; cytokine measurement; cell migration assays Nature communications High 29500416
2020 SIPA1 promotes transcription of EPAS1 (HIF-2α) and upregulates multiple glycolysis-related genes, shifting ATP production from oxidative phosphorylation to aerobic glycolysis. Knockdown of SIPA1 suppresses tumor metastasis in vitro and in vivo. SIPA1 overexpression and knockdown in breast cancer cells; metabolic flux assays; qRT-PCR for HIF-2α and glycolysis genes; in vivo metastasis assay Frontiers in cell and developmental biology Medium 35096814
2020 SIPA1 promotes stemness features of breast cancer cells by increasing SMAD2 and SMAD3 expression, leading to upregulation of stemness transcription factors. Blocking SMAD3 phosphorylation with the inhibitor SIS3 abolishes SIPA1-induced stemness and restores chemotherapy sensitivity. SIPA1 overexpression and knockdown; tumorsphere formation assay; Western blot for SMAD2/3; pharmacological SMAD3 inhibition; chemotherapy sensitivity assays in vitro and in vivo Stem cell research Medium 33296812
2020 Methylation of the CpG island in the Sipa1 promoter-proximal elements inversely correlates with SIPA1 protein expression in breast cancer cells. Demethylation by 5-Aza-CdR increases SIPA1 expression and promotes EMT; SIPA1 knockdown reverses EMT in MDA-MB-231 cells while SIPA1 overexpression promotes EMT in MCF7 cells. Bisulfite sequencing; 5-Aza-CdR treatment; SIPA1 overexpression and knockdown; Western blot for EMT markers Journal of cell science Medium 32193333
2021 A novel nuclear localization region (NLR, residues 140-179) of SIPA1 containing His160 is required for nuclear import; deletion of NLR prevents nuclear localization, abolishes SIPA1-dependent cell migration promotion and upregulation of ABCB1/MDR1, and eliminates SIPA1-promoted epirubicin resistance in breast cancer cells. Deletion mutagenesis; subcellular localization by imaging; Western blot for MDR1; cell migration and proliferation assays; drug sensitivity assay International journal of biological macromolecules Medium 33753200
2021 SIPA1 promotes tight junction-based barrier function and cancer metastasis in lung cancer by maintaining MET protein levels (not transcript) through regulation of Grb2, SOCS, and PKCμ, which control MET internalization and recycling. SIPA1 knockdown impairs MET-dependent barrier function and reduces invasion. SIPA1 knockdown in lung cancer cell lines; Western blot for MET protein and transcript; barrier function assay; invasion assay; HGF/MET pathway analysis Cancers Medium 33917539
2022 SIPA1 promotes MYH9 (myosin-9) transcription in breast cancer cells, elevating myosin-9 in cancer-derived extracellular vesicles (EVs). These EVs enhance macrophage migration and tumor infiltration, and blocking myosin-9 suppresses macrophage infiltration. SIPA1 knockdown; EV isolation; Western blot for myosin-9 in cells and EVs; macrophage migration assay in vitro and in vivo; blebbistatin (myosin-9 inhibitor) treatment Biology Medium 35453742
2023 SIPA1 functions as a transcription factor, binding DNA via a defined DNA-binding region (DBR) that recognizes a TGAGTCAB motif (confirmed by EMSA). Importin β1 interacts with SIPA1 upon fibronectin treatment. SIPA1 directly regulates transcription of fibronectin 1 (FN1) in a DBR-dependent manner in vitro and in vivo, promoting TNBC cell migration and invasion. Electrophoretic mobility shift assay (EMSA); Co-immunoprecipitation with Importin β1; ChIP; DBR deletion mutants; in vivo tumor xenograft; single-cell RNA sequencing of clinical specimens Oncogene High 37500797
2023 Rasa3 and Sipa1 are critical Rap1-inactivating proteins in T cells controlling lymphocyte trafficking. Combined loss of Rasa3 and Sipa1 induces spontaneous Rap1 activation, causing T cell trapping in lung capillaries via LFA-1-dependent adhesion (rescued by LFA-1 antibody, talin1 loss, or Rap1 loss), and impairs T cell egress from lymph nodes despite normal entry and fast migration. Double knockout mouse model; LFA-1 antibody blockade; genetic epistasis (talin1 KO, Rap1 KO rescue); intravital imaging; flow cytometry Frontiers in immunology High 37545505
2024 SIPA1 promotes EMT in colorectal cancer by activating STAT3 phosphorylation, which leads to STAT3 nuclear translocation. Pharmacological STAT3 inhibition (STTITA) in SIPA1-overexpressing cells reverses EMT marker changes, placing SIPA1 upstream of STAT3 in this pathway. SIPA1 knockdown and overexpression; STAT3 inhibitor co-treatment; Western blot for pSTAT3, EMT markers; proliferation and migration assays Heliyon Medium 39130435
2024 SIPA1 activates STAT3 phosphorylation in Müller cells, leading to nuclear STAT3 translocation and upregulation of VEGF expression; SIPA1-dependent VEGF secretion promotes retinal vascular endothelial cell mobility. STAT3 inhibition (STATTIC) blocks SIPA1's effect on VEGF expression. SIPA1 overexpression in Müller cells; STAT3 inhibitor (STATTIC) co-treatment; Western blot for pSTAT3 and VEGF; endothelial cell mobility assay Heliyon Medium 38312659
2025 UCHL3 deubiquitinase directly binds SIPA1 and removes K48-linked polyubiquitin chains from SIPA1 at lysine 805, protecting it from proteasomal degradation. The E3 ligase ITCH promotes K48-linked ubiquitination and degradation of SIPA1, acting antagonistically to UCHL3. TRIM21 targets UCHL3 for proteasomal degradation, thus regulating the UCHL3-ITCH-SIPA1 axis. Co-immunoprecipitation; ubiquitination assays with K48-specific linkage analysis; site-directed mutagenesis (K805); proteasome inhibitor experiments; overexpression and knockdown in CRC cells Cancer letters High 41412211
2025 Sipa1 in cardiac fibroblasts promotes production of CCL2, CCL7, and GM-CSF early after myocardial infarction via a noncanonical RasGRP2-Ras-JNK signaling pathway (independent of canonical Rap1 signaling), facilitating accumulation of Ly6C-high monocytes and CCR2+ macrophages and worsening post-MI cardiac outcomes. Cardiac fibroblast-specific Sipa1 conditional knockout prevents excessive inflammation and adverse remodeling. Sipa1 global knockout and cardiac fibroblast-specific conditional knockout mice; bone marrow transplantation; flow cytometry; transcriptomic analysis; cytokine measurement; pharmacological/genetic dissection of signaling (RasGRP2-Ras-JNK vs Rap1 pathway) Circulation research High 40567222

Source papers

Stage 0 corpus · 95 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 LAF1 ubiquitination by COP1 controls photomorphogenesis and is stimulated by SPA1. Nature 381 12827204
2003 The COP1-SPA1 interaction defines a critical step in phytochrome A-mediated regulation of HY5 activity. Genes & development 365 14597662
1999 SPA1, a WD-repeat protein specific to phytochrome A signal transduction. Science (New York, N.Y.) 215 10205059
1999 Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion. The Journal of biological chemistry 147 10373454
1998 SPA1: a new genetic locus involved in phytochrome A-specific signal transduction. The Plant cell 142 9477570
2005 Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nature genetics 136 16142231
2004 Differences in biochemical properties and in biological function between human SP-A1 and SP-A2 variants, and the impact of ozone-induced oxidation. Biochemistry 86 15065867
2005 Differences in the translation efficiency and mRNA stability mediated by 5'-UTR splice variants of human SP-A1 and SP-A2 genes. American journal of physiology. Lung cellular and molecular physiology 85 15894557
2003 The SPA1-like proteins SPA3 and SPA4 repress photomorphogenesis in the light. The Plant journal : for cell and molecular biology 83 12887588
2003 AF-6 controls integrin-mediated cell adhesion by regulating Rap1 activation through the specific recruitment of Rap1GTP and SPA-1. The Journal of biological chemistry 82 12590145
2004 Aquaporin-2 trafficking is regulated by PDZ-domain containing protein SPA-1. FEBS letters 78 15196935
2004 SP-A1 and SP-A2 variants differentially enhance association of Pseudomonas aeruginosa with rat alveolar macrophages. American journal of physiology. Lung cellular and molecular physiology 76 15377498
1994 Human SP-A1 and SP-A2 genes are differentially regulated during development and by cAMP and glucocorticoids. The American journal of physiology 71 8179013
2009 Genetic complexity of the human innate host defense molecules, surfactant protein A1 (SP-A1) and SP-A2--impact on function. Critical reviews in eukaryotic gene expression 70 19392648
2007 Surfactant protein A2 (SP-A2) variants expressed in CHO cells stimulate phagocytosis of Pseudomonas aeruginosa more than do SP-A1 variants. Infection and immunity 66 17220308
1994 Characterization of mRNA transcripts and organization of human SP-A1 and SP-A2 genes. The American journal of physiology 65 8179012
2010 Humanized SFTPA1 and SFTPA2 transgenic mice reveal functional divergence of SP-A1 and SP-A2: formation of tubular myelin in vivo requires both gene products. The Journal of biological chemistry 64 20048345
2004 Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and subcellular localization. Molecular and cellular biology 63 15456879
1988 SPA1: a gene important for chromosome segregation and other mitotic functions in S. cerevisiae. Cell 60 3044610
2006 Characterization of a human surfactant protein A1 (SP-A1) gene-specific antibody; SP-A1 content variation among individuals of varying age and pulmonary health. American journal of physiology. Lung cellular and molecular physiology 57 17189324
1998 Differential regulation of SP-A1 and SP-A2 genes by cAMP, glucocorticoids, and insulin. The American journal of physiology 50 9486201
1998 Regulation of expression of human SP-A1 and SP-A2 genes in fetal lung explant culture. Biochimica et biophysica acta 47 9689918
2016 Human Pulmonary Surfactant Protein SP-A1 Provides Maximal Efficiency of Lung Interfacial Films. Biophysical journal 44 27508436
2007 Structural and functional differences among human surfactant proteins SP-A1, SP-A2 and co-expressed SP-A1/SP-A2: role of supratrimeric oligomerization. The Biochemical journal 44 17542781
2014 Nuclear SIPA1 activates integrin β1 promoter and promotes invasion of breast cancer cells. Oncogene 39 24704834
2002 Recombinant human SP-A1 and SP-A2 proteins have different carbohydrate-binding characteristics. American journal of physiology. Lung cellular and molecular physiology 39 12505869
2004 Rap1 and SPA-1 in hematologic malignancy. Trends in molecular medicine 38 15310461
2021 Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions. Frontiers in immunology 35 34484180
2011 SPA-1 controls the invasion and metastasis of human prostate cancer. Cancer science 35 21251160
2001 Both human SP-A1 and Sp-A2 genes are expressed in small and large intestine. Pediatric pathology & molecular medicine 34 11552738
2018 Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm. Blood advances 33 29514790
2007 Differential effects of human SP-A1 and SP-A2 variants on phospholipid monolayers containing surfactant protein B. Biochimica et biophysica acta 33 17678872
2012 Genetic complexity of the human surfactant-associated proteins SP-A1 and SP-A2. Gene 32 23069847
2002 Association of polymorphisms in the collagen region of human SP-A1 and SP-A2 genes with pulmonary tuberculosis in Indian population. Clinical chemistry and laboratory medicine 32 12476938
2013 Differences in the alveolar macrophage proteome in transgenic mice expressing human SP-A1 and SP-A2. Journal of proteomics and genomics research 29 24729982
2008 Spa-1 (Sipa1) and Rap signaling in leukemia and cancer metastasis. Cancer science 28 19037996
2017 SIPA1 promotes invasion and migration in human oral squamous cell carcinoma by ITGB1 and MMP7. Experimental cell research 27 28237246
2009 Polymorphisms in MMP9 and SIPA1 are associated with increased risk of nodal metastases in early-stage cervical cancer. Gynecologic oncology 27 19906411
2012 Expression of signal-induced proliferation-associated gene 1 (SIPA1), a RapGTPase-activating protein, is increased in colorectal cancer and has diverse effects on functions of colorectal cancer cells. Cancer genomics & proteomics 26 22990111
2007 Inhibition of hemagglutination activity of influenza A viruses by SP-A1 and SP-A2 variants expressed in CHO cells. Medical microbiology and immunology 26 17520282
2009 SPA1 and DET1 act together to control photomorphogenesis throughout plant development. Planta 25 20041285
2011 SP-A1, SP-A2 and SP-D gene polymorphisms in severe acute respiratory syncytial infection in Chilean infants. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 24 21601013
1999 Glucocorticoid inhibition of human SP-A1 promoter activity in NCI-H441 cells. The Biochemical journal 21 10229660
1998 Differential regulation of baboon SP-A1 and SP-A2 genes: structural and functional analysis of 5'-flanking DNA. The American journal of physiology 21 9843844
2006 Role of SPA-1 in phenotypes of chronic myelogenous leukemia induced by BCR-ABL-expressing hematopoietic progenitors in a mouse model. Cancer research 20 17047059
2009 Genetic variation in SIPA1 in relation to breast cancer risk and survival after breast cancer diagnosis. International journal of cancer 19 19089925
2022 SIPA1 Enhances Aerobic Glycolysis Through HIF-2α Pathway to Promote Breast Cancer Metastasis. Frontiers in cell and developmental biology 18 35096814
2019 Differential Effects of Human SP-A1 and SP-A2 on the BAL Proteome and Signaling Pathways in Response to Klebsiella pneumoniae and Ozone Exposure. Frontiers in immunology 18 30972061
2019 Major Effect of Oxidative Stress on the Male, but Not Female, SP-A1 Type II Cell miRNome. Frontiers in immunology 18 31354704
2010 Human SP-A1 (SFTPA1) variant-specific 3' UTRs and poly(A) tail differentially affect the in vitro translation of a reporter gene. American journal of physiology. Lung cellular and molecular physiology 16 20693318
2003 A single round PCR method for genotyping human surfactant protein (SP)-A1, SP-A2 and SP-D gene alleles. Tissue antigens 16 12753670
2001 Light-induced growth promotion by SPA1 counteracts phytochrome-mediated growth inhibition during de-etiolation. Plant physiology 16 11457980
2009 Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility. BMC cancer 15 19765277
1997 Mitogen-inducible SIPA1 is mapped to the conserved syntenic groups of chromosome 19 in mouse and chromosome 11q13.3 centromeric to BCL1 in human. Genomics 15 9027487
2013 Sipa1 promoter polymorphism predicts risk and metastasis of lung cancer in Chinese. Molecular carcinogenesis 14 23661532
2004 Specific recruitment of SPA-1 to the immunological synapse: involvement of actin-bundling protein actinin. Immunology letters 14 15081616
2022 Extracellular Vesicles Derived from SIPA1high Breast Cancer Cells Enhance Macrophage Infiltration and Cancer Metastasis through Myosin-9. Biology 13 35453742
2020 The Importance of Redox Status in the Frame of Lifestyle Approaches and the Genetics of the Lung Innate Immune Molecules, SP-A1 and SP-A2, on Differential Outcomes of COVID-19 Infection. Antioxidants (Basel, Switzerland) 13 32854247
2008 Spa-1 regulates the maintenance and differentiation of human embryonic stem cells. The International journal of developmental biology 13 18033671
2000 Induction of AP-1 binding to intron 1 of SP-A1 and SP-A2 is implicated in the phorbol ester inhibition of human SP-A promoter activity. Experimental lung research 13 10914330
2021 Functional comparison of the WD-repeat domains of SPA1 and COP1 in suppression of photomorphogenesis. Plant, cell & environment 12 34251043
2020 5-Aza-2'-deoxycytidine advances the epithelial-mesenchymal transition of breast cancer cells by demethylating Sipa1 promoter-proximal elements. Journal of cell science 12 32193333
2020 SIPA1 enhances SMAD2/3 expression to maintain stem cell features in breast cancer cells. Stem cell research 12 33296812
2021 A novel nuclear localization region in SIPA1 determines protein nuclear distribution and epirubicin-sensitivity of breast cancer cells. International journal of biological macromolecules 10 33753200
2013 Case-only analyses of the associations between polymorphisms in the metastasis-modifying genes BRMS1 and SIPA1 and breast tumor characteristics, lymph node metastasis, and survival. Breast cancer research and treatment 10 23771732
2018 Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells. Nature communications 9 29500416
2013 Association of SIPA1 545 C > T polymorphism with survival in Chinese women with metastatic breast cancer. Frontiers of medicine 9 23358895
2022 SIPA1 Regulates LINC01615 to Promote Metastasis in Triple-Negative Breast Cancer. Cancers 8 36230738
2021 SIPA1 Is a Modulator of HGF/MET Induced Tumour Metastasis via the Regulation of Tight Junction-Based Cell to Cell Barrier Function. Cancers 7 33917539
2016 The contribution of SIPA1 and RRP1B germline polymorphisms to breast cancer phenotype, lymph node status and survival in a group of Lithuanian young breast cancer patients. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 7 26901824
2020 The role of SIPA1 in the development of cancer and metastases (Review). Molecular and clinical oncology 6 32789016
2020 Differences in the alveolar macrophage toponome in humanized SP-A1 and SP-A2 transgenic mice. JCI insight 6 33141765
2008 Bcr/Abl P190 interaction with Spa-1, a GTPase activating protein for the small GTPase Rap1. International journal of molecular medicine 6 18813851
2020 Using toponomics to characterize phenotypic diversity in alveolar macrophages from male mice treated with exogenous SP-A1. Biomarker research 5 32082572
2023 A novel transcription factor SIPA1: identification and verification in triple-negative breast cancer. Oncogene 4 37500797
2023 The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes. Frontiers in immunology 4 37545505
2015 Suppression of SIPA-1 expression may reduce bladder cancer invasion and metastasis via the downregulation of E-cadherin and ZO-1. Experimental and therapeutic medicine 4 26889242
2025 Sipa1 Drives a Maladaptive Fibroblast-Myeloid Axis After Myocardial Infarction. Circulation research 3 40567222
2020 Study on the Relationship Between Respiratory Distress Syndrome and SP-A1 (rs1059057) Gene Polymorphism in Mongolian Very Premature Infants. Frontiers in pediatrics 3 32257981
2013 The association of SIPA1 gene polymorphisms with breast cancer risk: evidence from published studies. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 3 24006220
2022 The alveolar macrophage toponome of female SP-A knockout mice differs from that of males before and after SP-A1 rescue. Scientific reports 2 35322074
2022 SIPA1 boosts migration and proliferation, and blocks apoptosis of glioma by activating the phosphorylation of the FAK signaling pathway. Journal of medical biochemistry 2 35431649
2015 High SIPA-1 expression in proximal tubules of human kidneys under pathological conditions. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 2 25673195
2025 A TRIM21-UCHL3-ITCH-SIPA1 axis promotes colorectal cancer growth and metastasis. Cancer letters 1 41412211
2024 SIPA1 promotes angiogenesis by regulating VEGF secretion in Müller cells through STAT3 activation. Heliyon 1 38312659
2024 SIPA1 promotes epithelial-mesenchymal transition in colorectal cancer through STAT3 activation. Heliyon 1 39130435
2024 DDIT4 promotes erythroid differentiation and coordinates with SIPA1 to regulate erythroid proliferation in bone marrow of high altitude erythrocytosis. Life sciences 1 39488268
1998 Genomic organization and cloning of the human homologue of murine Sipa-1. Gene 1 9651531
1996 Overexpression and functional analysis of a mitogen-inducible nuclear GTPase activating protein, Spa-1. The international journal of biochemistry & cell biology 1 9022283
1996 [Regulatory mechanisms of lymphocyte proliferation: roles of Spa-1 gene]. Human cell 1 9183624
2026 Involvement of the Light Signalling Components HY5 and BIC1,2 and SPA1 in Plant Responses to Elevated Daytime UV-B Doses. International journal of molecular sciences 0 41828652
2025 [Expression of SIPA1 in colorectal cancer and its impact on its biological behavior]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 0 40692252
2024 Characterization of PIF4 Phosphorylation by SPA1. Methods in molecular biology (Clifton, N.J.) 0 38594537
2022 Erratum: [Corrigendum] Suppression of SIPA‑1 expression may reduce bladder cancer invasion and metastasis via the downregulation of E‑cadherin and ZO‑1. Experimental and therapeutic medicine 0 36277150
2000 Genomic sequencing reveals the structure of the Kcnk6 and map3k11 genes and their close vicinity to the sipa1 gene on mouse chromosome 19. Cytogenetics and cell genetics 0 10894943

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