{"gene":"PRR11","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2012,"finding":"PRR11 is periodically expressed in a cell cycle-dependent manner; RNAi-mediated silencing causes significant S phase arrest and growth retardation in HeLa and lung cancer cells, establishing a role in cell cycle progression.","method":"RNAi knockdown, flow cytometry, colony formation, xenograft","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA knockdown with defined S-phase arrest phenotype, colony formation, and in vivo xenograft; single lab but multiple orthogonal readouts","pmids":["23246489"],"is_preprint":false},{"year":2015,"finding":"PRR11 and SKA2 are oriented head-to-head with an intergenic spacer <500 bp; a minimal 80-bp region functions as a core bidirectional promoter, and NF-Y directly binds and transactivates this promoter to drive expression of both genes.","method":"5'-RACE, serial luciferase reporter assays, EMSA, ChIP, siRNA-mediated NF-Y depletion","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (EMSA, ChIP, luciferase reporter, RACE) in a single study rigorously establishing the promoter architecture and NF-Y binding","pmids":["26162986"],"is_preprint":false},{"year":2015,"finding":"PRR11 is expressed largely in the cytoplasm; its expression starts to increase in late S phase and is retained until just before mitotic telophase. siRNA knockdown causes arrest in the late S phase and G2/M, leading to mitotic defects (multipolar spindles, multiple nuclei). Forced PRR11 expression induces premature chromatin condensation (PCC) and apoptosis.","method":"Immunofluorescence, siRNA knockdown, cell synchronization, flow cytometry, dNTP supplementation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunofluorescence localization linked to functional consequence, siRNA knockdown with multiple cell-cycle phenotype readouts; single lab","pmids":["25666944"],"is_preprint":false},{"year":2017,"finding":"p53 negatively regulates PRR11-SKA2 bidirectional transcription indirectly through NF-Y: wild-type p53 (but not mutant p53) represses the promoter in an NF-Y binding site-dependent manner; co-IP shows p53 associates with NF-Y in lung cancer cells; ChIP shows p53 reduces NF-Y occupancy at the PRR11-SKA2 promoter; NF-YB depletion attenuates p53-mediated repression.","method":"Luciferase reporter assay, deletion/mutation analysis, co-immunoprecipitation, ChIP, siRNA depletion","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, ChIP, reporter assay, mutagenesis, siRNA rescue) establish the p53–NF-Y–PRR11 regulatory axis","pmids":["28257042"],"is_preprint":false},{"year":2017,"finding":"PRR11 silencing in NSCLC cells inactivates the Akt/mTOR signaling pathway, enhances autophagosome formation, and upregulates LC3-II while downregulating p62, demonstrating a role in autophagy regulation.","method":"siRNA knockdown, immunoblotting (LC3-II, p62, p-Akt, p-mTOR), CCK-8, clone formation assay","journal":"Genes & diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, western blot readouts only, no pathway rescue or reconstitution","pmids":["30258945"],"is_preprint":false},{"year":2019,"finding":"p53 (wild-type) represses the PRR11-SKA2 bidirectional promoter in breast cancer cells; adriamycin-induced p53 activation reduces PRR11 and SKA2 expression; NF-Y is essential for PRR11 but not SKA2 expression in this context; PRR11/SKA2 knockdown dysregulates downstream genes CDK6, TPM3, and USP12.","method":"Luciferase reporter assay, drug-induced p53 activation, siRNA, western blot, qRT-PCR","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus endogenous p53 activation experiment; single lab with two orthogonal methods","pmids":["30760381"],"is_preprint":false},{"year":2020,"finding":"Cytoplasmic PRR11 associates with and recruits the ARP2/3 complex, facilitating F-actin polymerization and organization in NSCLC cells; dysregulation leads to abnormal nuclear lamina assembly and chromatin reorganization. Truncation mapping showed deletion of either N or C terminus abrogates F-actin effects; deletion of aa 100–184 or 100–200 induces actin comet tails. ARP2/3 inhibition abolishes PRR11 overexpression-induced F-actin changes.","method":"Immunofluorescence, actin polymerization assay, siRNA knockdown, truncation/deletion mutants, ARP2/3 inhibitor","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro actin polymerization assay, domain mapping with truncation mutants, pharmacological inhibitor rescue; multiple orthogonal methods in a single rigorous study","pmids":["32169900"],"is_preprint":false},{"year":2020,"finding":"The proline-rich motif of PRR11 interacts with the p85α regulatory subunit of PI3K, suppressing p85α homodimerization and thereby enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K, driving estrogen-independent proliferation and endocrine resistance in ER+ breast cancer.","method":"Co-IP, functional proliferation assays, PI3K inhibitor sensitivity assays, genetic knockdown/overexpression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic co-IP identifying PRR11–p85α interaction, p85α homodimerization assay, IRS1 binding assay, PI3K inhibitor sensitivity; multiple orthogonal methods in a high-quality peer-reviewed study","pmids":["33127913"],"is_preprint":false},{"year":2021,"finding":"PRR11 recruits and co-localizes with Arp2 at membrane protrusions to promote filopodia formation (but not lamellipodia); deletion of the proline-rich region 2 (aa 185–200) abrogates filopodia formation. PRR11 depletion increases active integrin β1 on the cell surface and reduces FAK-Y397 phosphorylation, repressing focal adhesion turnover and cell motility in NSCLC cells.","method":"siRNA knockdown, immunofluorescence/co-localization, PRR11 deletion mutants, flow cytometry (active integrin β1), western blot (pFAK)","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization plus domain deletion mapping plus downstream signaling readout; single lab","pmids":["35005120"],"is_preprint":false},{"year":2021,"finding":"PRR11 interacts with E2F1 protein and promotes degradation/reduces the stability of E2F1 in ccRCC cells, thereby affecting cell cycle progression; c-Myc transcription factor binds the PRR11 promoter and promotes PRR11 expression in ccRCC.","method":"Co-immunoprecipitation, protein stability assay, ChIP (c-Myc at PRR11 promoter), siRNA knockdown","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishing PRR11–E2F1 interaction and stability assay; single lab, peer-reviewed","pmids":["34499617"],"is_preprint":false},{"year":2021,"finding":"PRR11 interacts with E2F1 on the PTTG1 promoter region (as shown by co-IP and promoter assays) to increase PTTG1 transcription, and PRR11 can be detected in the nucleus; this PRR11-E2F1-PTTG1 axis promotes cell cycle progression and cancer cell proliferation.","method":"Co-immunoprecipitation, RNA-seq, ChIP/promoter analysis, siRNA knockdown, nuclear fractionation","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus nuclear localization plus RNA-seq downstream target identification; single lab","pmids":["36060253"],"is_preprint":false},{"year":2021,"finding":"Hedgehog pathway inhibition (GLI1/2 inhibitor GANT-61 or GLI1/2-siRNA) decreases PRR11 and SKA2 expression in lung squamous cell carcinoma cells, placing PRR11 expression downstream of GLI1/2 in the Hedgehog pathway.","method":"siRNA knockdown of GLI1/2, pharmacological inhibitor (GANT-61), RNA sequencing, RT-PCR","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect epistasis (inhibitor plus siRNA reduces PRR11 expression); no direct GLI binding to PRR11 promoter shown; single lab","pmids":["33477943"],"is_preprint":false},{"year":2021,"finding":"lncRNA CCDC26 interacts with CELF2 RNA-binding protein (confirmed by RNA pull-down and RNA-IP) and upregulates PRR11 protein by sponging miR-195a-5p via circRNA_ANKIB1; elevated PRR11 activates PI3K/AKT and NF-κB pathways in myeloid leukemia cells.","method":"RNA pull-down, RNA-IP, luciferase reporter, miRNA inhibitor, western blot","journal":"Cell transplantation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA pull-down confirms lncRNA–CELF2 interaction, but PRR11 regulation is indirect (ceRNA cascade); single lab","pmids":["33439746"],"is_preprint":false},{"year":2023,"finding":"ELF1 transcription factor binds the PRR11 promoter and promotes its transcriptional activation; PRR11 in turn recruits the ARP2/3 complex to promote F-actin polymerization and FAK activation in trophoblast cells, supporting proliferation and motility.","method":"ChIP (ELF1 at PRR11 promoter), western blot, immunofluorescence, MTT, Transwell assay","journal":"American journal of reproductive immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP shows ELF1 promoter binding but mechanistic follow-up is limited; single lab, single study","pmids":["37641376"],"is_preprint":false},{"year":2024,"finding":"PRR11 directly binds to and stabilizes DHODH protein; PRR11 inhibits binding of E3 ubiquitin ligase HERC4 to DHODH, suppressing HERC4-mediated polyubiquitination of DHODH at K306, thereby preventing its proteasomal degradation and conferring ferroptosis resistance in glioblastoma cells.","method":"Co-IP, ubiquitination assay, site-directed mutagenesis (K306), PRR11 depletion, in vitro and in vivo functional assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — co-IP identifying PRR11–DHODH interaction, ubiquitination assay with K306 mutagenesis, HERC4 recruitment assay, in vivo validation; multiple orthogonal methods in a single rigorous study","pmids":["38838551"],"is_preprint":false},{"year":2025,"finding":"PRR11 interacts with GRB2 (while SKA2 interacts with EGFR) to robustly activate the PI3K-AKT pathway in lung cancer cells; CRISPRi-mediated repression of the entire PRR11-SKA2-miR301a/454 transcription unit inhibits cell growth, cell cycle progression, and cell motility.","method":"Co-immunoprecipitation (PRR11–GRB2 interaction), CRISPRi, functional cell assays, mouse tumor models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying PRR11–GRB2 interaction with CRISPRi functional validation; single study, peer-reviewed","pmids":["41309933"],"is_preprint":false},{"year":2026,"finding":"OTUB1 deubiquitinase interacts with PRR11 and stabilizes it in retinoblastoma cells (identified by co-IP/mass spectrometry); PRR11 suppresses DKK3 expression, leading to aberrant Wnt/β-catenin pathway activation, cyclin D1 upregulation, and S/G2M cell cycle progression.","method":"Co-IP/mass spectrometry, proteomic analysis, functional knockdown, in vitro and in vivo tumor assays","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP/MS identifies OTUB1–PRR11 interaction; proteomic downstream target (DKK3) identified; single lab","pmids":["41575699"],"is_preprint":false},{"year":2018,"finding":"miR-195 directly targets PRR11 mRNA (validated by dual-luciferase assay); PRR11 overexpression abrogates the suppressive effects of miR-195 on prostate cancer cell proliferation, tube formation, and cell cycling, establishing PRR11 as a functional downstream target of the miR-195 axis.","method":"Dual-luciferase assay, RNA microarray, in vitro proliferation/tube formation assays, xenograft model","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase validates direct miRNA–3'UTR interaction; rescue experiment confirms functional link; single lab","pmids":["29393495"],"is_preprint":false},{"year":2018,"finding":"lncRNA DLX6-AS1 acts as a competing endogenous RNA (ceRNA) for miR-144, upregulating PRR11 expression; PRR11 overexpression reverses DLX6-AS1-knockdown-mediated suppression of NSCLC cell proliferation and invasion, placing PRR11 downstream of the DLX6-AS1/miR-144 axis.","method":"Luciferase reporter assay, siRNA knockdown, western blot, qRT-PCR, xenograft assay","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter and rescue experiment support ceRNA mechanism; indirect regulation of PRR11; single lab","pmids":["30551440"],"is_preprint":false},{"year":2020,"finding":"USP34 deubiquitinase knockdown significantly downregulates PRR11 protein levels in pancreatic cancer PANC-1 cells, suggesting USP34 promotes PRR11 protein stability; this is accompanied by inactivation of p38 MAPK signaling.","method":"shRNA knockdown of USP34, western blot (PRR11, p-p38), xenograft in vivo model","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot association only; direct deubiquitination of PRR11 by USP34 not demonstrated; single lab","pmids":["32110045"],"is_preprint":false}],"current_model":"PRR11 is a cell-cycle-regulated, proline-rich cytoplasmic (and partially nuclear) protein that drives S-to-G2/M progression by: (1) recruiting the ARP2/3 complex via its proline-rich region to promote F-actin polymerization, filopodia formation, FAK activation, and nuclear lamina stability; (2) interacting via its proline-rich motif with the p85α regulatory subunit of PI3K to suppress p85α homodimerization, enhance IRS1-associated p110-p85α activity, and activate PI3K-AKT signaling (also mediated through interaction with GRB2); (3) stabilizing DHODH by blocking HERC4-mediated K306 polyubiquitination, thereby conferring ferroptosis resistance; (4) interacting with E2F1 to modulate its protein stability and transcriptional output (including PTTG1); (5) being stabilized by the deubiquitinase OTUB1; and (6) being transcriptionally regulated by a bidirectional promoter co-activated by NF-Y and repressed by p53 (through displacement of NF-Y), with additional upstream inputs from c-Myc, ELF1, and GLI1/2."},"narrative":{"mechanistic_narrative":"PRR11 is a cell-cycle-regulated, predominantly cytoplasmic proline-rich protein whose expression peaks from late S phase to mitosis and is required for orderly S-to-G2/M progression, with loss causing S-phase and G2/M arrest and mitotic defects such as multipolar spindles and multinucleation [PMID:23246489, PMID:25666944]. Mechanistically, cytoplasmic PRR11 uses its proline-rich region to associate with and recruit the ARP2/3 complex, driving F-actin polymerization and filopodia formation, supporting FAK-Y397 activation and focal adhesion turnover, and maintaining proper nuclear lamina assembly; domain mapping shows the proline-rich region (notably aa 185–200) is essential for these actin-dependent effects [PMID:32169900, PMID:35005120]. PRR11 also nucleates growth-factor signaling: its proline-rich motif binds the PI3K regulatory subunit p85α to suppress p85α homodimerization and enhance IRS1-associated p110–p85α PI3K activity, and it interacts with GRB2, together activating PI3K-AKT signaling [PMID:33127913, PMID:41309933]. In the nucleus, PRR11 interacts with E2F1 to modulate its stability and transcriptional output, including activation of PTTG1 [PMID:34499617, PMID:36060253]. PRR11 additionally stabilizes DHODH by blocking HERC4-mediated K306 polyubiquitination, conferring ferroptosis resistance [PMID:38838551], and its own protein level is controlled by the deubiquitinase OTUB1 [PMID:41575699]. PRR11 is transcribed from a bidirectional promoter shared head-to-head with SKA2 that is directly bound and transactivated by NF-Y and repressed by wild-type p53 through displacement of NF-Y [PMID:26162986, PMID:28257042].","teleology":[{"year":2012,"claim":"Established that PRR11 is a cell-cycle-dependent gene functionally required for cell proliferation, defining it as a candidate cell-cycle regulator rather than a passively co-expressed transcript.","evidence":"RNAi knockdown with flow cytometry, colony formation, and xenograft in HeLa and lung cancer cells","pmids":["23246489"],"confidence":"Medium","gaps":["No molecular mechanism for the S-phase arrest identified","Subcellular localization and partners unknown at this stage"]},{"year":2015,"claim":"Defined where and when PRR11 acts by showing it is largely cytoplasmic, accumulating from late S phase to telophase, and that its loss produces late-S/G2/M arrest and mitotic catastrophe.","evidence":"Immunofluorescence, cell synchronization, siRNA knockdown, flow cytometry in cell lines","pmids":["25666944"],"confidence":"Medium","gaps":["No direct molecular effectors of the mitotic phenotype identified","Mechanism of premature chromatin condensation unexplained"]},{"year":2015,"claim":"Resolved how PRR11 transcription is wired by mapping an 80-bp bidirectional promoter shared with SKA2 that NF-Y directly binds and transactivates, explaining co-regulation of the two genes.","evidence":"5'-RACE, serial luciferase reporters, EMSA, ChIP, NF-Y depletion","pmids":["26162986"],"confidence":"High","gaps":["Upstream signals controlling NF-Y at this promoter not yet defined","Functional relationship between PRR11 and SKA2 proteins not addressed"]},{"year":2017,"claim":"Connected PRR11 to tumor-suppressor control by showing wild-type p53 represses the bidirectional promoter indirectly through association with NF-Y and reduction of NF-Y occupancy.","evidence":"Luciferase reporters, mutagenesis, co-IP, ChIP, siRNA depletion in lung cancer cells","pmids":["28257042"],"confidence":"High","gaps":["Whether p53 acts at this promoter in non-lung tissues not tested","Does not establish PRR11 protein-level consequences of p53 activation"]},{"year":2017,"claim":"Linked PRR11 to Akt/mTOR and autophagy, indicating a signaling role beyond transcriptional regulation.","evidence":"siRNA knockdown with immunoblotting of LC3-II, p62, p-Akt, p-mTOR in NSCLC cells","pmids":["30258945"],"confidence":"Low","gaps":["No pathway rescue or reconstitution; correlation only","Direct molecular link between PRR11 and Akt/mTOR not shown here"]},{"year":2018,"claim":"Identified upstream non-coding regulators by validating PRR11 mRNA as a direct miR-195 target and as a functional effector downstream of the DLX6-AS1/miR-144 ceRNA axis.","evidence":"Dual-luciferase assays, microarray, rescue proliferation assays, xenografts","pmids":["29393495","30551440"],"confidence":"Medium","gaps":["ceRNA model (DLX6-AS1/miR-144) is indirect and single-lab","Physiological relevance of these miRNA interactions in normal tissue untested"]},{"year":2019,"claim":"Extended the p53–NF-Y repression of PRR11 to breast cancer and showed endogenous p53 induction lowers PRR11, while defining downstream dysregulated targets (CDK6, TPM3, USP12).","evidence":"Reporter assays, adriamycin-induced p53 activation, siRNA, western blot, qRT-PCR","pmids":["30760381"],"confidence":"Medium","gaps":["Downstream gene changes are correlative, not mechanistically dissected","Direct vs indirect control of each target unresolved"]},{"year":2020,"claim":"Provided the first direct molecular function for cytoplasmic PRR11 by showing it recruits the ARP2/3 complex to drive F-actin polymerization and proper nuclear lamina assembly, with domain mapping localizing the activity.","evidence":"Actin polymerization assay, immunofluorescence, truncation/deletion mutants, ARP2/3 inhibitor rescue in NSCLC cells","pmids":["32169900"],"confidence":"High","gaps":["Whether PRR11 directly nucleates or acts as an ARP2/3 adaptor not fully resolved","Link between actin defects and the cell-cycle phenotype not mechanistically closed"]},{"year":2020,"claim":"Defined a growth-factor signaling mechanism: PRR11's proline-rich motif binds p85α to block its homodimerization, enhancing IRS1-associated PI3K activity and driving endocrine resistance.","evidence":"Co-IP, p85α homodimerization assay, IRS1 binding assay, PI3K inhibitor sensitivity in ER+ breast cancer","pmids":["33127913"],"confidence":"High","gaps":["Structural basis of the PRR11–p85α interaction not determined","Relative contribution of PI3K vs actin functions to proliferation unresolved"]},{"year":2020,"claim":"Associated PRR11 protein stability with deubiquitinase USP34, hinting at post-translational regulation.","evidence":"shRNA knockdown of USP34, western blot of PRR11 and p-p38, xenograft","pmids":["32110045"],"confidence":"Low","gaps":["Direct deubiquitination of PRR11 by USP34 not demonstrated","Western blot association only, no reciprocal validation"]},{"year":2021,"claim":"Refined the cytoskeletal role to filopodia (not lamellipodia) formation via Arp2 co-localization and showed PRR11 controls integrin β1 activation, FAK phosphorylation, and focal adhesion turnover.","evidence":"siRNA, co-localization, deletion mutants, flow cytometry for active integrin β1, pFAK western blot in NSCLC cells","pmids":["35005120"],"confidence":"Medium","gaps":["Mechanism linking PRR11 to integrin β1 activation state unknown","Single lab; in vivo motility role not tested"]},{"year":2021,"claim":"Revealed a nuclear, transcription-modulating arm in which PRR11 interacts with E2F1 to affect its stability and, on the PTTG1 promoter, increase PTTG1 transcription, with c-Myc identified as an upstream activator of PRR11.","evidence":"Co-IP, protein stability assays, ChIP, RNA-seq, nuclear fractionation in ccRCC and other cancer cells","pmids":["34499617","36060253"],"confidence":"Medium","gaps":["Opposing reports of E2F1 destabilization vs cooperative promoter activity not reconciled","How a proline-rich protein modulates E2F1 stability mechanistically unclear"]},{"year":2021,"claim":"Placed PRR11 expression downstream of additional oncogenic transcriptional inputs (GLI1/2 Hedgehog signaling) and non-coding cascades (lncRNA CCDC26/CELF2/circRNA_ANKIB1).","evidence":"GLI1/2 inhibitor and siRNA with RNA-seq; RNA pull-down and RNA-IP in leukemia cells","pmids":["33477943","33439746"],"confidence":"Low","gaps":["GLI direct binding to the PRR11 promoter not shown (epistasis only)","ncRNA regulation of PRR11 is indirect and single-lab"]},{"year":2023,"claim":"Showed the ELF1→PRR11→ARP2/3 axis operates outside cancer, supporting trophoblast proliferation and motility.","evidence":"ChIP for ELF1, western blot, immunofluorescence, MTT and Transwell in trophoblast cells","pmids":["37641376"],"confidence":"Low","gaps":["Mechanistic follow-up limited; single study","Physiological role in placentation not established"]},{"year":2024,"claim":"Uncovered a metabolic/redox function: PRR11 binds DHODH and blocks HERC4-mediated K306 polyubiquitination, stabilizing DHODH and conferring ferroptosis resistance.","evidence":"Co-IP, ubiquitination assays with K306 mutagenesis, HERC4 recruitment assay, in vivo glioblastoma models","pmids":["38838551"],"confidence":"High","gaps":["Whether this ferroptosis role generalizes beyond glioblastoma untested","How cytoplasmic PRR11 balances actin, PI3K, and DHODH functions unresolved"]},{"year":2025,"claim":"Added GRB2 as a direct PRR11 partner driving PI3K-AKT activation and showed CRISPRi repression of the entire PRR11-SKA2-miR301a/454 unit suppresses growth, cycle, and motility.","evidence":"Co-IP for PRR11–GRB2, CRISPRi, functional assays, mouse tumor models in lung cancer","pmids":["41309933"],"confidence":"Medium","gaps":["Relative contribution of GRB2 vs p85α to PI3K activation not dissected","Individual gene contributions within the repressed unit not separated"]},{"year":2026,"claim":"Identified OTUB1 as a deubiquitinase that stabilizes PRR11 and linked PRR11 to Wnt/β-catenin activation via DKK3 suppression in retinoblastoma.","evidence":"Co-IP/mass spectrometry, proteomic analysis, knockdown, in vitro and in vivo tumor assays","pmids":["41575699"],"confidence":"Medium","gaps":["Direct deubiquitination of PRR11 by OTUB1 vs indirect stabilization not fully separated","Mechanism by which PRR11 suppresses DKK3 unknown"]},{"year":null,"claim":"It remains unresolved how PRR11's multiple molecular activities — cytoskeletal ARP2/3 recruitment, PI3K-AKT signaling, E2F1/transcriptional modulation, and DHODH stabilization — are integrated within a single cell-cycle program, and whether these are coupled or context-specific functions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PRR11 or its proline-rich interaction surfaces","No unifying assay testing which activity is rate-limiting for the cell-cycle phenotype","Native protein complexes containing PRR11 not characterized stoichiometrically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,7,8,15]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[6,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["SKA2","ARP2/3","PIK3R1","GRB2","E2F1","DHODH","HERC4","OTUB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96HE9","full_name":"Proline-rich protein 11","aliases":[],"length_aa":360,"mass_kda":40.1,"function":"Plays a critical role in cell cycle progression","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96HE9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRR11","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTG1","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRR11","total_profiled":1310},"omim":[{"mim_id":"616674","title":"SPINDLE- AND KINETOCHORE-ASSOCIATED COMPLEX, SUBUNIT 2; SKA2","url":"https://www.omim.org/entry/616674"},{"mim_id":"615920","title":"PROLINE-RICH PROTEIN 11; PRR11","url":"https://www.omim.org/entry/615920"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":17.0},{"tissue":"lymphoid tissue","ntpm":19.1}],"url":"https://www.proteinatlas.org/search/PRR11"},"hgnc":{"alias_symbol":["FLJ11029"],"prev_symbol":[]},"alphafold":{"accession":"Q96HE9","domains":[{"cath_id":"1.20.5","chopping":"69-102","consensus_level":"medium","plddt":86.3479,"start":69,"end":102},{"cath_id":"1.10.287","chopping":"104-136","consensus_level":"medium","plddt":88.437,"start":104,"end":136}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HE9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HE9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HE9-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRR11","jax_strain_url":"https://www.jax.org/strain/search?query=PRR11"},"sequence":{"accession":"Q96HE9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96HE9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96HE9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HE9"}},"corpus_meta":[{"pmid":"23246489","id":"PMC_23246489","title":"PRR11 is a novel gene implicated in cell cycle progression and lung cancer.","date":"2012","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23246489","citation_count":71,"is_preprint":false},{"pmid":"26162986","id":"PMC_26162986","title":"The gene pair PRR11 and SKA2 shares a NF-Y-regulated bidirectional promoter and contributes to lung cancer development.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26162986","citation_count":54,"is_preprint":false},{"pmid":"30551440","id":"PMC_30551440","title":"Knockdown of lncRNA DLX6-AS1 inhibits cell proliferation, migration and invasion while promotes apoptosis by downregulating PRR11 expression and upregulating miR-144 in non-small cell lung cancer.","date":"2018","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30551440","citation_count":47,"is_preprint":false},{"pmid":"29393495","id":"PMC_29393495","title":"miR-195 inhibits cell proliferation and angiogenesis in human prostate cancer by downregulating PRR11 expression.","date":"2018","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/29393495","citation_count":43,"is_preprint":false},{"pmid":"33127913","id":"PMC_33127913","title":"Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33127913","citation_count":37,"is_preprint":false},{"pmid":"25666944","id":"PMC_25666944","title":"PRR11 regulates late-S to G2/M phase progression and induces premature chromatin condensation (PCC).","date":"2015","source":"Biochemical and biophysical research 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/32565988","citation_count":14,"is_preprint":false},{"pmid":"31040705","id":"PMC_31040705","title":"Overexpression of PRR11 promotes tumorigenic capability and is associated with progression in esophageal squamous cell carcinoma.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31040705","citation_count":11,"is_preprint":false},{"pmid":"35005120","id":"PMC_35005120","title":"PRR11 induces filopodia formation and promotes cell motility via recruiting ARP2/3 complex in non-small cell lung cancer cells.","date":"2021","source":"Genes & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/35005120","citation_count":11,"is_preprint":false},{"pmid":"34659555","id":"PMC_34659555","title":"Down-regulation of PRR11 affects the proliferation, migration and invasion of osteosarcoma by inhibiting the Wnt/β-catenin pathway.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34659555","citation_count":11,"is_preprint":false},{"pmid":"31258760","id":"PMC_31258760","title":"The oncogenic potential of PRR11 gene in Tongue Squamous Cell Carcinoma cells.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31258760","citation_count":10,"is_preprint":false},{"pmid":"35126622","id":"PMC_35126622","title":"miR-204-5p Hampers Breast Cancer Malignancy and Affects the Cell Cycle by Targeting PRR11.","date":"2022","source":"Computational and mathematical methods in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35126622","citation_count":10,"is_preprint":false},{"pmid":"35181621","id":"PMC_35181621","title":"PRR11 Promotes Proliferation and Migration of Colorectal Cancer through Activating the EGFR/ERK/AKT Pathway via Increasing CTHRC1.","date":"2022","source":"Annals of clinical and laboratory science","url":"https://pubmed.ncbi.nlm.nih.gov/35181621","citation_count":9,"is_preprint":false},{"pmid":"34379360","id":"PMC_34379360","title":"PRR11 unveiled as a top candidate biomarker within the RBM3-regulated transcriptome in pancreatic cancer.","date":"2021","source":"The journal of pathology. Clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/34379360","citation_count":9,"is_preprint":false},{"pmid":"34488538","id":"PMC_34488538","title":"MicroRNA-26b-5p suppresses the proliferation of tongue squamous cell carcinoma via targeting proline rich 11 (PRR11).","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/34488538","citation_count":9,"is_preprint":false},{"pmid":"36551227","id":"PMC_36551227","title":"PRR11 in Malignancies: Biological Activities and Targeted Therapies.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36551227","citation_count":6,"is_preprint":false},{"pmid":"33057583","id":"PMC_33057583","title":"Ultrasonic irradiation and SonoVue microbubbles-mediated RNA interference targeting PRR11 inhibits breast cancer cells proliferation and metastasis, but promotes apoptosis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/33057583","citation_count":6,"is_preprint":false},{"pmid":"36060253","id":"PMC_36060253","title":"PRR11 promotes cell proliferation by regulating PTTG1 through interacting with E2F1 transcription factor in pan-cancer.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36060253","citation_count":6,"is_preprint":false},{"pmid":"33477943","id":"PMC_33477943","title":"HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33477943","citation_count":5,"is_preprint":false},{"pmid":"40062654","id":"PMC_40062654","title":"PRR11 Promotes Bladder Cancer Growth and Metastasis by Facilitating G1/S Progression and Epithelial-Mesenchymal Transition.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40062654","citation_count":2,"is_preprint":false},{"pmid":"36727626","id":"PMC_36727626","title":"Proline-rich 11 (PRR11) promotes the progression of cutaneous squamous cell carcinoma by activating the EGFR signaling pathway.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/36727626","citation_count":2,"is_preprint":false},{"pmid":"37641376","id":"PMC_37641376","title":"ELF1/PRR11/ARP2/3 promoted trophoblast cells proliferation and motility in early pregnancy.","date":"2023","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/37641376","citation_count":1,"is_preprint":false},{"pmid":"41309933","id":"PMC_41309933","title":"Overexpressed PRR11-SKA2-miR301a/454 bidirectional transcription unit essentially and coordinately promotes PI3K-AKT pathway activation and lung cancer progression.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41309933","citation_count":1,"is_preprint":false},{"pmid":"36825583","id":"PMC_36825583","title":"[Corrigendum] miR‑195 inhibits cell proliferation and angiogenesis in human prostate cancer by downregulating PRR11 expression.","date":"2023","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/36825583","citation_count":1,"is_preprint":false},{"pmid":"41575699","id":"PMC_41575699","title":"PRR11 as a newly identified oncogenic driver in retinoblastoma.","date":"2026","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41575699","citation_count":0,"is_preprint":false},{"pmid":"37811303","id":"PMC_37811303","title":"Retracted: miR-204-5p Hampers Breast Cancer Malignancy and Affects the Cell Cycle by Targeting PRR11.","date":"2023","source":"Computational and mathematical methods in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37811303","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20559,"output_tokens":5028,"usd":0.068548,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13286,"output_tokens":5253,"usd":0.098877,"stage2_stop_reason":"end_turn"},"total_usd":0.167425,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"PRR11 is periodically expressed in a cell cycle-dependent manner; RNAi-mediated silencing causes significant S phase arrest and growth retardation in HeLa and lung cancer cells, establishing a role in cell cycle progression.\",\n      \"method\": \"RNAi knockdown, flow cytometry, colony formation, xenograft\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA knockdown with defined S-phase arrest phenotype, colony formation, and in vivo xenograft; single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"23246489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRR11 and SKA2 are oriented head-to-head with an intergenic spacer <500 bp; a minimal 80-bp region functions as a core bidirectional promoter, and NF-Y directly binds and transactivates this promoter to drive expression of both genes.\",\n      \"method\": \"5'-RACE, serial luciferase reporter assays, EMSA, ChIP, siRNA-mediated NF-Y depletion\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (EMSA, ChIP, luciferase reporter, RACE) in a single study rigorously establishing the promoter architecture and NF-Y binding\",\n      \"pmids\": [\"26162986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRR11 is expressed largely in the cytoplasm; its expression starts to increase in late S phase and is retained until just before mitotic telophase. siRNA knockdown causes arrest in the late S phase and G2/M, leading to mitotic defects (multipolar spindles, multiple nuclei). Forced PRR11 expression induces premature chromatin condensation (PCC) and apoptosis.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown, cell synchronization, flow cytometry, dNTP supplementation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunofluorescence localization linked to functional consequence, siRNA knockdown with multiple cell-cycle phenotype readouts; single lab\",\n      \"pmids\": [\"25666944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p53 negatively regulates PRR11-SKA2 bidirectional transcription indirectly through NF-Y: wild-type p53 (but not mutant p53) represses the promoter in an NF-Y binding site-dependent manner; co-IP shows p53 associates with NF-Y in lung cancer cells; ChIP shows p53 reduces NF-Y occupancy at the PRR11-SKA2 promoter; NF-YB depletion attenuates p53-mediated repression.\",\n      \"method\": \"Luciferase reporter assay, deletion/mutation analysis, co-immunoprecipitation, ChIP, siRNA depletion\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (co-IP, ChIP, reporter assay, mutagenesis, siRNA rescue) establish the p53–NF-Y–PRR11 regulatory axis\",\n      \"pmids\": [\"28257042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PRR11 silencing in NSCLC cells inactivates the Akt/mTOR signaling pathway, enhances autophagosome formation, and upregulates LC3-II while downregulating p62, demonstrating a role in autophagy regulation.\",\n      \"method\": \"siRNA knockdown, immunoblotting (LC3-II, p62, p-Akt, p-mTOR), CCK-8, clone formation assay\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, western blot readouts only, no pathway rescue or reconstitution\",\n      \"pmids\": [\"30258945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p53 (wild-type) represses the PRR11-SKA2 bidirectional promoter in breast cancer cells; adriamycin-induced p53 activation reduces PRR11 and SKA2 expression; NF-Y is essential for PRR11 but not SKA2 expression in this context; PRR11/SKA2 knockdown dysregulates downstream genes CDK6, TPM3, and USP12.\",\n      \"method\": \"Luciferase reporter assay, drug-induced p53 activation, siRNA, western blot, qRT-PCR\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus endogenous p53 activation experiment; single lab with two orthogonal methods\",\n      \"pmids\": [\"30760381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cytoplasmic PRR11 associates with and recruits the ARP2/3 complex, facilitating F-actin polymerization and organization in NSCLC cells; dysregulation leads to abnormal nuclear lamina assembly and chromatin reorganization. Truncation mapping showed deletion of either N or C terminus abrogates F-actin effects; deletion of aa 100–184 or 100–200 induces actin comet tails. ARP2/3 inhibition abolishes PRR11 overexpression-induced F-actin changes.\",\n      \"method\": \"Immunofluorescence, actin polymerization assay, siRNA knockdown, truncation/deletion mutants, ARP2/3 inhibitor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro actin polymerization assay, domain mapping with truncation mutants, pharmacological inhibitor rescue; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32169900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The proline-rich motif of PRR11 interacts with the p85α regulatory subunit of PI3K, suppressing p85α homodimerization and thereby enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K, driving estrogen-independent proliferation and endocrine resistance in ER+ breast cancer.\",\n      \"method\": \"Co-IP, functional proliferation assays, PI3K inhibitor sensitivity assays, genetic knockdown/overexpression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic co-IP identifying PRR11–p85α interaction, p85α homodimerization assay, IRS1 binding assay, PI3K inhibitor sensitivity; multiple orthogonal methods in a high-quality peer-reviewed study\",\n      \"pmids\": [\"33127913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRR11 recruits and co-localizes with Arp2 at membrane protrusions to promote filopodia formation (but not lamellipodia); deletion of the proline-rich region 2 (aa 185–200) abrogates filopodia formation. PRR11 depletion increases active integrin β1 on the cell surface and reduces FAK-Y397 phosphorylation, repressing focal adhesion turnover and cell motility in NSCLC cells.\",\n      \"method\": \"siRNA knockdown, immunofluorescence/co-localization, PRR11 deletion mutants, flow cytometry (active integrin β1), western blot (pFAK)\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization plus domain deletion mapping plus downstream signaling readout; single lab\",\n      \"pmids\": [\"35005120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRR11 interacts with E2F1 protein and promotes degradation/reduces the stability of E2F1 in ccRCC cells, thereby affecting cell cycle progression; c-Myc transcription factor binds the PRR11 promoter and promotes PRR11 expression in ccRCC.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, ChIP (c-Myc at PRR11 promoter), siRNA knockdown\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishing PRR11–E2F1 interaction and stability assay; single lab, peer-reviewed\",\n      \"pmids\": [\"34499617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRR11 interacts with E2F1 on the PTTG1 promoter region (as shown by co-IP and promoter assays) to increase PTTG1 transcription, and PRR11 can be detected in the nucleus; this PRR11-E2F1-PTTG1 axis promotes cell cycle progression and cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, ChIP/promoter analysis, siRNA knockdown, nuclear fractionation\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus nuclear localization plus RNA-seq downstream target identification; single lab\",\n      \"pmids\": [\"36060253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hedgehog pathway inhibition (GLI1/2 inhibitor GANT-61 or GLI1/2-siRNA) decreases PRR11 and SKA2 expression in lung squamous cell carcinoma cells, placing PRR11 expression downstream of GLI1/2 in the Hedgehog pathway.\",\n      \"method\": \"siRNA knockdown of GLI1/2, pharmacological inhibitor (GANT-61), RNA sequencing, RT-PCR\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect epistasis (inhibitor plus siRNA reduces PRR11 expression); no direct GLI binding to PRR11 promoter shown; single lab\",\n      \"pmids\": [\"33477943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"lncRNA CCDC26 interacts with CELF2 RNA-binding protein (confirmed by RNA pull-down and RNA-IP) and upregulates PRR11 protein by sponging miR-195a-5p via circRNA_ANKIB1; elevated PRR11 activates PI3K/AKT and NF-κB pathways in myeloid leukemia cells.\",\n      \"method\": \"RNA pull-down, RNA-IP, luciferase reporter, miRNA inhibitor, western blot\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA pull-down confirms lncRNA–CELF2 interaction, but PRR11 regulation is indirect (ceRNA cascade); single lab\",\n      \"pmids\": [\"33439746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ELF1 transcription factor binds the PRR11 promoter and promotes its transcriptional activation; PRR11 in turn recruits the ARP2/3 complex to promote F-actin polymerization and FAK activation in trophoblast cells, supporting proliferation and motility.\",\n      \"method\": \"ChIP (ELF1 at PRR11 promoter), western blot, immunofluorescence, MTT, Transwell assay\",\n      \"journal\": \"American journal of reproductive immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP shows ELF1 promoter binding but mechanistic follow-up is limited; single lab, single study\",\n      \"pmids\": [\"37641376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRR11 directly binds to and stabilizes DHODH protein; PRR11 inhibits binding of E3 ubiquitin ligase HERC4 to DHODH, suppressing HERC4-mediated polyubiquitination of DHODH at K306, thereby preventing its proteasomal degradation and conferring ferroptosis resistance in glioblastoma cells.\",\n      \"method\": \"Co-IP, ubiquitination assay, site-directed mutagenesis (K306), PRR11 depletion, in vitro and in vivo functional assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — co-IP identifying PRR11–DHODH interaction, ubiquitination assay with K306 mutagenesis, HERC4 recruitment assay, in vivo validation; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"38838551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRR11 interacts with GRB2 (while SKA2 interacts with EGFR) to robustly activate the PI3K-AKT pathway in lung cancer cells; CRISPRi-mediated repression of the entire PRR11-SKA2-miR301a/454 transcription unit inhibits cell growth, cell cycle progression, and cell motility.\",\n      \"method\": \"Co-immunoprecipitation (PRR11–GRB2 interaction), CRISPRi, functional cell assays, mouse tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying PRR11–GRB2 interaction with CRISPRi functional validation; single study, peer-reviewed\",\n      \"pmids\": [\"41309933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OTUB1 deubiquitinase interacts with PRR11 and stabilizes it in retinoblastoma cells (identified by co-IP/mass spectrometry); PRR11 suppresses DKK3 expression, leading to aberrant Wnt/β-catenin pathway activation, cyclin D1 upregulation, and S/G2M cell cycle progression.\",\n      \"method\": \"Co-IP/mass spectrometry, proteomic analysis, functional knockdown, in vitro and in vivo tumor assays\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP/MS identifies OTUB1–PRR11 interaction; proteomic downstream target (DKK3) identified; single lab\",\n      \"pmids\": [\"41575699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-195 directly targets PRR11 mRNA (validated by dual-luciferase assay); PRR11 overexpression abrogates the suppressive effects of miR-195 on prostate cancer cell proliferation, tube formation, and cell cycling, establishing PRR11 as a functional downstream target of the miR-195 axis.\",\n      \"method\": \"Dual-luciferase assay, RNA microarray, in vitro proliferation/tube formation assays, xenograft model\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase validates direct miRNA–3'UTR interaction; rescue experiment confirms functional link; single lab\",\n      \"pmids\": [\"29393495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"lncRNA DLX6-AS1 acts as a competing endogenous RNA (ceRNA) for miR-144, upregulating PRR11 expression; PRR11 overexpression reverses DLX6-AS1-knockdown-mediated suppression of NSCLC cell proliferation and invasion, placing PRR11 downstream of the DLX6-AS1/miR-144 axis.\",\n      \"method\": \"Luciferase reporter assay, siRNA knockdown, western blot, qRT-PCR, xenograft assay\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter and rescue experiment support ceRNA mechanism; indirect regulation of PRR11; single lab\",\n      \"pmids\": [\"30551440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP34 deubiquitinase knockdown significantly downregulates PRR11 protein levels in pancreatic cancer PANC-1 cells, suggesting USP34 promotes PRR11 protein stability; this is accompanied by inactivation of p38 MAPK signaling.\",\n      \"method\": \"shRNA knockdown of USP34, western blot (PRR11, p-p38), xenograft in vivo model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot association only; direct deubiquitination of PRR11 by USP34 not demonstrated; single lab\",\n      \"pmids\": [\"32110045\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRR11 is a cell-cycle-regulated, proline-rich cytoplasmic (and partially nuclear) protein that drives S-to-G2/M progression by: (1) recruiting the ARP2/3 complex via its proline-rich region to promote F-actin polymerization, filopodia formation, FAK activation, and nuclear lamina stability; (2) interacting via its proline-rich motif with the p85α regulatory subunit of PI3K to suppress p85α homodimerization, enhance IRS1-associated p110-p85α activity, and activate PI3K-AKT signaling (also mediated through interaction with GRB2); (3) stabilizing DHODH by blocking HERC4-mediated K306 polyubiquitination, thereby conferring ferroptosis resistance; (4) interacting with E2F1 to modulate its protein stability and transcriptional output (including PTTG1); (5) being stabilized by the deubiquitinase OTUB1; and (6) being transcriptionally regulated by a bidirectional promoter co-activated by NF-Y and repressed by p53 (through displacement of NF-Y), with additional upstream inputs from c-Myc, ELF1, and GLI1/2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRR11 is a cell-cycle-regulated, predominantly cytoplasmic proline-rich protein whose expression peaks from late S phase to mitosis and is required for orderly S-to-G2/M progression, with loss causing S-phase and G2/M arrest and mitotic defects such as multipolar spindles and multinucleation [#0, #2]. Mechanistically, cytoplasmic PRR11 uses its proline-rich region to associate with and recruit the ARP2/3 complex, driving F-actin polymerization and filopodia formation, supporting FAK-Y397 activation and focal adhesion turnover, and maintaining proper nuclear lamina assembly; domain mapping shows the proline-rich region (notably aa 185–200) is essential for these actin-dependent effects [#6, #8]. PRR11 also nucleates growth-factor signaling: its proline-rich motif binds the PI3K regulatory subunit p85α to suppress p85α homodimerization and enhance IRS1-associated p110–p85α PI3K activity, and it interacts with GRB2, together activating PI3K-AKT signaling [#7, #15]. In the nucleus, PRR11 interacts with E2F1 to modulate its stability and transcriptional output, including activation of PTTG1 [#9, #10]. PRR11 additionally stabilizes DHODH by blocking HERC4-mediated K306 polyubiquitination, conferring ferroptosis resistance [#14], and its own protein level is controlled by the deubiquitinase OTUB1 [#16]. PRR11 is transcribed from a bidirectional promoter shared head-to-head with SKA2 that is directly bound and transactivated by NF-Y and repressed by wild-type p53 through displacement of NF-Y [#1, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that PRR11 is a cell-cycle-dependent gene functionally required for cell proliferation, defining it as a candidate cell-cycle regulator rather than a passively co-expressed transcript.\",\n      \"evidence\": \"RNAi knockdown with flow cytometry, colony formation, and xenograft in HeLa and lung cancer cells\",\n      \"pmids\": [\"23246489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for the S-phase arrest identified\", \"Subcellular localization and partners unknown at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined where and when PRR11 acts by showing it is largely cytoplasmic, accumulating from late S phase to telophase, and that its loss produces late-S/G2/M arrest and mitotic catastrophe.\",\n      \"evidence\": \"Immunofluorescence, cell synchronization, siRNA knockdown, flow cytometry in cell lines\",\n      \"pmids\": [\"25666944\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular effectors of the mitotic phenotype identified\", \"Mechanism of premature chromatin condensation unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how PRR11 transcription is wired by mapping an 80-bp bidirectional promoter shared with SKA2 that NF-Y directly binds and transactivates, explaining co-regulation of the two genes.\",\n      \"evidence\": \"5'-RACE, serial luciferase reporters, EMSA, ChIP, NF-Y depletion\",\n      \"pmids\": [\"26162986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling NF-Y at this promoter not yet defined\", \"Functional relationship between PRR11 and SKA2 proteins not addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected PRR11 to tumor-suppressor control by showing wild-type p53 represses the bidirectional promoter indirectly through association with NF-Y and reduction of NF-Y occupancy.\",\n      \"evidence\": \"Luciferase reporters, mutagenesis, co-IP, ChIP, siRNA depletion in lung cancer cells\",\n      \"pmids\": [\"28257042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53 acts at this promoter in non-lung tissues not tested\", \"Does not establish PRR11 protein-level consequences of p53 activation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked PRR11 to Akt/mTOR and autophagy, indicating a signaling role beyond transcriptional regulation.\",\n      \"evidence\": \"siRNA knockdown with immunoblotting of LC3-II, p62, p-Akt, p-mTOR in NSCLC cells\",\n      \"pmids\": [\"30258945\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No pathway rescue or reconstitution; correlation only\", \"Direct molecular link between PRR11 and Akt/mTOR not shown here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified upstream non-coding regulators by validating PRR11 mRNA as a direct miR-195 target and as a functional effector downstream of the DLX6-AS1/miR-144 ceRNA axis.\",\n      \"evidence\": \"Dual-luciferase assays, microarray, rescue proliferation assays, xenografts\",\n      \"pmids\": [\"29393495\", \"30551440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ceRNA model (DLX6-AS1/miR-144) is indirect and single-lab\", \"Physiological relevance of these miRNA interactions in normal tissue untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the p53–NF-Y repression of PRR11 to breast cancer and showed endogenous p53 induction lowers PRR11, while defining downstream dysregulated targets (CDK6, TPM3, USP12).\",\n      \"evidence\": \"Reporter assays, adriamycin-induced p53 activation, siRNA, western blot, qRT-PCR\",\n      \"pmids\": [\"30760381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream gene changes are correlative, not mechanistically dissected\", \"Direct vs indirect control of each target unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the first direct molecular function for cytoplasmic PRR11 by showing it recruits the ARP2/3 complex to drive F-actin polymerization and proper nuclear lamina assembly, with domain mapping localizing the activity.\",\n      \"evidence\": \"Actin polymerization assay, immunofluorescence, truncation/deletion mutants, ARP2/3 inhibitor rescue in NSCLC cells\",\n      \"pmids\": [\"32169900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRR11 directly nucleates or acts as an ARP2/3 adaptor not fully resolved\", \"Link between actin defects and the cell-cycle phenotype not mechanistically closed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a growth-factor signaling mechanism: PRR11's proline-rich motif binds p85α to block its homodimerization, enhancing IRS1-associated PI3K activity and driving endocrine resistance.\",\n      \"evidence\": \"Co-IP, p85α homodimerization assay, IRS1 binding assay, PI3K inhibitor sensitivity in ER+ breast cancer\",\n      \"pmids\": [\"33127913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PRR11–p85α interaction not determined\", \"Relative contribution of PI3K vs actin functions to proliferation unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Associated PRR11 protein stability with deubiquitinase USP34, hinting at post-translational regulation.\",\n      \"evidence\": \"shRNA knockdown of USP34, western blot of PRR11 and p-p38, xenograft\",\n      \"pmids\": [\"32110045\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct deubiquitination of PRR11 by USP34 not demonstrated\", \"Western blot association only, no reciprocal validation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the cytoskeletal role to filopodia (not lamellipodia) formation via Arp2 co-localization and showed PRR11 controls integrin β1 activation, FAK phosphorylation, and focal adhesion turnover.\",\n      \"evidence\": \"siRNA, co-localization, deletion mutants, flow cytometry for active integrin β1, pFAK western blot in NSCLC cells\",\n      \"pmids\": [\"35005120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PRR11 to integrin β1 activation state unknown\", \"Single lab; in vivo motility role not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a nuclear, transcription-modulating arm in which PRR11 interacts with E2F1 to affect its stability and, on the PTTG1 promoter, increase PTTG1 transcription, with c-Myc identified as an upstream activator of PRR11.\",\n      \"evidence\": \"Co-IP, protein stability assays, ChIP, RNA-seq, nuclear fractionation in ccRCC and other cancer cells\",\n      \"pmids\": [\"34499617\", \"36060253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing reports of E2F1 destabilization vs cooperative promoter activity not reconciled\", \"How a proline-rich protein modulates E2F1 stability mechanistically unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed PRR11 expression downstream of additional oncogenic transcriptional inputs (GLI1/2 Hedgehog signaling) and non-coding cascades (lncRNA CCDC26/CELF2/circRNA_ANKIB1).\",\n      \"evidence\": \"GLI1/2 inhibitor and siRNA with RNA-seq; RNA pull-down and RNA-IP in leukemia cells\",\n      \"pmids\": [\"33477943\", \"33439746\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"GLI direct binding to the PRR11 promoter not shown (epistasis only)\", \"ncRNA regulation of PRR11 is indirect and single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed the ELF1→PRR11→ARP2/3 axis operates outside cancer, supporting trophoblast proliferation and motility.\",\n      \"evidence\": \"ChIP for ELF1, western blot, immunofluorescence, MTT and Transwell in trophoblast cells\",\n      \"pmids\": [\"37641376\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic follow-up limited; single study\", \"Physiological role in placentation not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a metabolic/redox function: PRR11 binds DHODH and blocks HERC4-mediated K306 polyubiquitination, stabilizing DHODH and conferring ferroptosis resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination assays with K306 mutagenesis, HERC4 recruitment assay, in vivo glioblastoma models\",\n      \"pmids\": [\"38838551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this ferroptosis role generalizes beyond glioblastoma untested\", \"How cytoplasmic PRR11 balances actin, PI3K, and DHODH functions unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added GRB2 as a direct PRR11 partner driving PI3K-AKT activation and showed CRISPRi repression of the entire PRR11-SKA2-miR301a/454 unit suppresses growth, cycle, and motility.\",\n      \"evidence\": \"Co-IP for PRR11–GRB2, CRISPRi, functional assays, mouse tumor models in lung cancer\",\n      \"pmids\": [\"41309933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of GRB2 vs p85α to PI3K activation not dissected\", \"Individual gene contributions within the repressed unit not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified OTUB1 as a deubiquitinase that stabilizes PRR11 and linked PRR11 to Wnt/β-catenin activation via DKK3 suppression in retinoblastoma.\",\n      \"evidence\": \"Co-IP/mass spectrometry, proteomic analysis, knockdown, in vitro and in vivo tumor assays\",\n      \"pmids\": [\"41575699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deubiquitination of PRR11 by OTUB1 vs indirect stabilization not fully separated\", \"Mechanism by which PRR11 suppresses DKK3 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PRR11's multiple molecular activities — cytoskeletal ARP2/3 recruitment, PI3K-AKT signaling, E2F1/transcriptional modulation, and DHODH stabilization — are integrated within a single cell-cycle program, and whether these are coupled or context-specific functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PRR11 or its proline-rich interaction surfaces\", \"No unifying assay testing which activity is rate-limiting for the cell-cycle phenotype\", \"Native protein complexes containing PRR11 not characterized stoichiometrically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7, 8, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SKA2\", \"ARP2/3\", \"PIK3R1\", \"GRB2\", \"E2F1\", \"DHODH\", \"HERC4\", \"OTUB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}