Affinage

SEC23IP

SEC23-interacting protein · UniProt Q9Y6Y8

Length
1000 aa
Mass
111.1 kDa
Annotated
2026-06-10
58 papers in source corpus 9 papers cited in narrative 9 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

SEC23IP (p125A) is a mammalian ER exit site (ERES) protein that organizes the early secretory pathway and facilitates COPII-mediated ER-to-Golgi traffic (PMID:10400679, PMID:15623529). It was identified through its N-terminal proline-rich region, which binds the COPII inner coat subunit Sec23, with its central and C-terminal regions sharing homology with phosphatidic acid-preferring phospholipase A1 (PMID:10400679). SEC23IP localizes principally to ERES via its specific N-terminal region, and its depletion disrupts ERES organization and cis-Golgi structure (PMID:15623529). Mechanistically, SEC23IP bridges the COPII inner and outer coats: a distinct domain (residues 260–600) binds the C-terminal helical region of Sec31A, and most cytosolic SEC23IP exists in a preassembled ternary complex with Sec13/Sec31A (PMID:20679433). By simultaneously binding Sec23, Sec31, and PI4P on ERGIC/cis-Golgi acceptor membranes, it stabilizes donor-acceptor membrane apposition to promote COPII outer coat assembly and traffic of large cargoes such as fibrillar collagens (PMID:40463098). SEC23IP additionally functions as an adaptor that recruits VPS13B/COH1 to the ERES-Golgi interface, an interaction disrupted by Cohen syndrome-associated VPS13B mutations and required for tubular ERGIC carrier formation and procollagen export (PMID:39352497). In vivo, Sec23ip is essential for acrosome biogenesis during spermiogenesis (PMID:21640725), and it acts within the 14-3-3γ network to support cholesterol trafficking and steroidogenesis in Leydig cells (PMID:31875919).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1999 High

    Established SEC23IP as a Sec23-interacting protein of the early secretory pathway, defining the binding domain and a candidate enzymatic domain that placed it at the ER-Golgi interface.

    Evidence GST-fusion pulldown, yeast two-hybrid, and overexpression organelle morphology in mammalian cells

    PMID:10400679

    Open questions at the time
    • Did not localize endogenous protein or test loss-of-function
    • Phospholipase A1 homology not demonstrated to be catalytically active in p125 itself
    • Mechanism linking overexpression to ERGIC/Golgi disorganization unresolved
  2. 2000 Medium

    Mapped the Sec23-binding determinant to residues 135–259 and showed correct ERES/Golgi localization requires a larger region, while co-localization with p115 and GM130 connected SEC23IP to vesicle tethering machinery.

    Evidence Deletion mutant series and immunofluorescence co-localization in cultured cells

    PMID:11112430

    Open questions at the time
    • Co-localization does not establish direct interaction with tethering factors
    • Functional consequence of the localization determinant not tested by loss-of-function
  3. 2002 Medium

    Showed the phospholipase A1 homology domain of the p125 family is enzymatically active toward phosphatidic acid, using the paralog KIAA0725p which lacks the Sec23-binding region.

    Evidence In vitro binding and enzymatic activity assays on the paralog, overexpression morphology

    PMID:11788596

    Open questions at the time
    • p125/SEC23IP itself was not directly assayed for lipase activity
    • Physiological substrate and relevance of the lipase domain in vivo unknown
  4. 2004 High

    Localized SEC23IP specifically to ERES and demonstrated its requirement for ERES and cis-Golgi organization, distinguishing its structural role from bulk ER export.

    Evidence Immunofluorescence, electron microscopy, domain-swap chimeras, and RNAi with organelle morphology readouts

    PMID:15623529

    Open questions at the time
    • Did not identify the molecular partners mediating ERES organization
    • Why ER export was unaffected despite ERES disruption was not resolved
  5. 2010 High

    Revealed SEC23IP as a bridge between COPII inner and outer coats by mapping a separate Sec31A-binding domain and showing it forms a preassembled cytosolic ternary complex with Sec13/Sec31A.

    Evidence Co-immunoprecipitation, gel filtration, immunodepletion, and siRNA with ER-export and Golgi morphology assays

    PMID:20679433

    Open questions at the time
    • Stoichiometry and structure of the ternary complex not resolved
    • How the preassembled complex engages nascent COPII buds at ERES unclear
  6. 2011 High

    Defined a non-redundant in vivo role for Sec23ip in acrosome biogenesis, linking its secretory-pathway function to male fertility.

    Evidence Sec23ip knockout mouse with sperm morphology analysis and expression staging

    PMID:21640725

    Open questions at the time
    • Molecular basis of the acrosome defect (which cargo/trafficking step) not identified
    • Whether the phenotype reflects ERES/COPII function specifically was not tested
  7. 2020 Medium

    Connected Sec23ip to lipid trafficking by placing it in the 14-3-3γ network and showing its loss impairs cholesterol mobilization and steroidogenesis in Leydig cells.

    Evidence LC-MS interactome, siRNA knockdown, steroidogenesis and cholesterol-trafficking assays in MA-10 cells

    PMID:31875919

    Open questions at the time
    • Direct physical interaction with 14-3-3γ not validated reciprocally
    • Mechanism linking ERES function to cytoplasm-to-mitochondria cholesterol transport unclear
  8. 2024 High

    Identified SEC23IP as the ERES adaptor that recruits VPS13B/COH1 via its VAB domain, mechanistically linking the interaction to tubular ERGIC carrier formation, procollagen export, and Cohen syndrome.

    Evidence Co-IP, co-localization, knockout cell lines, procollagen trafficking, and disease-mutant binding assays

    PMID:39352497

    Open questions at the time
    • Whether VPS13B-mediated lipid transfer is the functional output at ERES not directly shown
    • Relationship between SEC23IP-VPS13B recruitment and COPII coat assembly not integrated
  9. 2025 High

    Reconstituted SEC23IP's coordinating mechanism, showing it simultaneously binds PI4P, Sec31, and Sec23 to stabilize donor-acceptor membrane contacts and drive COPII outer coat assembly for large cargo such as fibrillar collagen.

    Evidence Cell-free reconstitution, domain-swap chimeras, knockout cells, and secretome/transcriptome analysis (preprint)

    PMID:40463098

    Open questions at the time
    • Not yet peer-reviewed
    • Structural basis for simultaneous tripartite binding not resolved
    • How tunnel/carrier geometry accommodates large cargo not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved whether SEC23IP's phospholipase A1 homology domain is catalytically active in vivo and how this enzymatic potential integrates with its structural coat-bridging and PI4P-sensing roles.
  • No direct demonstration of SEC23IP lipase activity
  • No structure of SEC23IP in complex with COPII coat or membrane
  • Integration of lipid-modifying, adaptor, and coat-bridging functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 1 GO:0008289 lipid binding 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-9609507 Protein localization 2
Partners
SEC13SEC23ASEC31AVPS13BYWHAG
Complex memberships
COPII coatp125A-Sec13-Sec31A ternary complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 p125 (SEC23IP) was identified as a novel mammalian Sec23p-interacting protein, distinct from Sec24p. The N-terminal proline-rich region of p125 mediates binding to Sec23p, demonstrated by GST-fusion pulldown and yeast two-hybrid assay. The central and C-terminal regions share homology with phosphatidic acid-preferring phospholipase A1. Overexpression of p125 caused disorganization of the ER-Golgi intermediate compartment and Golgi apparatus, implicating it in the early secretory pathway. GST-fusion protein pulldown, yeast two-hybrid, transient overexpression in mammalian cells with organelle morphology assessment The Journal of biological chemistry High 10400679
2000 The proline-rich region (residues 135–259) of p125 is responsible for binding to Sec23p. For correct intracellular localization of p125 to ER-Golgi intermediate regions, a larger region (residues 135–1000) comprising both the proline-rich and phospholipase A1 homology regions is required. Expressed p125 principally colocalizes with p115 and GM130, both involved in vesicle tethering to Golgi membranes. Expression of deletion mutant series in cultured cells, co-localization by immunofluorescence Biochemical and biophysical research communications Medium 11112430
2004 p125 localizes principally to ER exit sites (ERES), as demonstrated by immunofluorescence and electron microscopy. The p125-specific N-terminal region is critical for ERES localization. RNAi-mediated depletion of p125 disrupted the organization of ERES and substantially disturbed the cis-Golgi compartment structure, while protein export from the ER occurred without significant delay. Immunofluorescence, electron microscopy, chimeric protein analysis, RNA interference knockdown with organelle morphology readout The Journal of biological chemistry High 15623529
2002 A paralog of p125, KIAA0725p, lacks the N-terminal proline-rich Sec23p-interacting region and does not bind Sec23p in vitro. KIAA0725p possesses phospholipase A1 activity preferentially for phosphatidic acid, indicating the lipase domain of the p125 family is enzymatically active, though p125 itself was not directly shown to have phospholipase activity in this study. In vitro binding analysis, overexpression with organelle morphology assessment, enzymatic activity assay on paralog The Journal of biological chemistry Medium 11788596
2010 p125A (SEC23IP) also interacts with the C-terminal region of Sec31A, in addition to its known interaction with Sec23A. The Sec31A-interacting domain maps to residues 260–600 of p125A, a distinct domain from that required for Sec23A interaction. Gel filtration and immunodepletion studies demonstrate that the majority of cytosolic p125A exists as a ternary complex with Sec13/Sec31A, suggesting p125A, Sec13, and Sec31A form preassembled heterohexamers in the cytosol. Silencing of p125A disrupted Golgi morphology and impaired protein export from the ER. Co-immunoprecipitation, gel filtration, immunodepletion, siRNA knockdown with Golgi morphology and ER-export assays The Journal of cell biology High 20679433
2011 p125/Sec23ip knockout male mice are subfertile; sperm from knockout mice have round heads and lack the acrosome. p125 is expressed at stages I–XII of spermatogenesis, similar to acrosome biogenesis proteins, establishing a required role for p125 in acrosome biogenesis during spermiogenesis. Gene knockout mouse model, sperm morphology analysis, immunostaining for expression staging FEBS letters High 21640725
2020 Sec23ip was identified as part of the 14-3-3γ protein network in MA-10 Leydig cells. siRNA-mediated silencing of Sec23ip decreased steroidogenesis, and in Sec23ip-silenced cells, cholesterol mobilization from the cytoplasmic membrane to mitochondria was impaired, indicating Sec23ip facilitates cholesterol trafficking for acute steroidogenesis. LC-MS proteomics (14-3-3γ interactome), siRNA knockdown, steroidogenesis assay, cholesterol trafficking assay Endocrinology Medium 31875919
2024 Sec23IP at ERES acts as a VPS13B/COH1 adaptor, recruiting VPS13B to ERES-Golgi interfaces via direct interaction with the VPS13 adaptor binding domain (VAB) of VPS13B. Disease-associated missense mutations in VPS13B-VAB impair binding to Sec23IP. Knockout of VPS13B or Sec23IP blocks formation of tubular ERGIC cargo carriers and delays ER export of procollagen, linking the Sec23IP-VPS13B interaction to collagen secretion and joint laxity in Cohen syndrome. Co-immunoprecipitation, co-localization imaging, knockout cell lines, procollagen trafficking assay, mutant binding analysis The Journal of cell biology High 39352497
2025 p125A (SEC23IP) bridges the COPII outer coat assembly to PI4P-rich ERGIC/cis-Golgi acceptor membranes by simultaneously binding phosphatidylinositol 4-phosphate (PI4P), Sec31, and Sec23. In cell-free reconstitutions, apposition of donor and acceptor membranes promoted Sec13/31 outer layer assembly, and p125A stabilized this donor-acceptor contact. Loss of p125A selectively destabilized COPII outer layer assembly and inhibited fibrillar collagen traffic from the ER, while a p125A chimera with a Golgi-targeted PI4P-binding domain could rescue outer layer assembly. The C-terminal helical domain of Sec31A is essential for its interaction with p125A at ERES. Cell-free reconstitution, domain-swap chimeras, p125A knockout cells, transcriptome and secretome analysis, fluorescence imaging of COPII dynamics bioRxivpreprint High 40463098

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Bombesin stimulation of p125 focal adhesion kinase tyrosine phosphorylation. Role of protein kinase C, Ca2+ mobilization, and the actin cytoskeleton. The Journal of biological chemistry 270 8314789
1997 NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn). The Journal of biological chemistry 218 9079653
1999 Pulsatile stretch activates mitogen-activated protein kinase (MAPK) family members and focal adhesion kinase (p125(FAK)) in cultured rat cardiac myocytes. Biochemical and biophysical research communications 126 10334907
1995 Differential effects of platelet-derived growth factor BB on p125 focal adhesion kinase and paxillin tyrosine phosphorylation and on cell migration in rabbit aortic vascular smooth muscle cells and Swiss 3T3 fibroblasts. The Journal of biological chemistry 111 7538114
1996 Bombesin, bradykinin, vasopressin, and phorbol esters rapidly and transiently activate Src family tyrosine kinases in Swiss 3T3 cells. Dissociation from tyrosine phosphorylation of p125 focal adhesion kinase. The Journal of biological chemistry 109 8910389
1996 Requirement for phosphatidylinositol 3'-kinase activity in platelet-derived growth factor-stimulated tyrosine phosphorylation of p125 focal adhesion kinase and paxillin. The Journal of biological chemistry 93 8631827
1999 p125 is a novel mammalian Sec23p-interacting protein with structural similarity to phospholipid-modifying proteins. The Journal of biological chemistry 90 10400679
1999 The naturally occurring mutants of DDB are impaired in stimulating nuclear import of the p125 subunit and E2F1-activated transcription. Molecular and cellular biology 88 10373543
2002 A novel phospholipase A1 with sequence homology to a mammalian Sec23p-interacting protein, p125. The Journal of biological chemistry 86 11788596
1998 Activation of human endothelial cells via S-endo-1 antigen (CD146) stimulates the tyrosine phosphorylation of focal adhesion kinase p125(FAK). The Journal of biological chemistry 86 9756930
2000 p125 focal adhesion kinase promotes malignant astrocytoma cell proliferation in vivo. Journal of cell science 84 11069767
2011 Coronavirus infection induces DNA replication stress partly through interaction of its nonstructural protein 13 with the p125 subunit of DNA polymerase δ. The Journal of biological chemistry 82 21918226
2004 p125 is localized in endoplasmic reticulum exit sites and involved in their organization. The Journal of biological chemistry 80 15623529
1999 Direct interaction of proliferating cell nuclear antigen with the p125 catalytic subunit of mammalian DNA polymerase delta. The Journal of biological chemistry 75 10480866
1998 Growth hormone stimulates the tyrosine phosphorylation and association of p125 focal adhesion kinase (FAK) with JAK2. Fak is not required for stat-mediated transcription. The Journal of biological chemistry 69 9553131
1996 Dissociation of mitogen-activated protein kinase activation from p125 focal adhesion kinase tyrosine phosphorylation in Swiss 3T3 cells stimulated by bombesin, lysophosphatidic acid, and platelet-derived growth factor. Molecular biology of the cell 60 8970151
1993 RNA insertions and gene duplications in the nonstructural protein p125 region of pestivirus strains and isolates in vitro and in vivo. Virology 54 8384762
2010 p125A exists as part of the mammalian Sec13/Sec31 COPII subcomplex to facilitate ER-Golgi transport. The Journal of cell biology 49 20679433
1992 Heterogeneous expression of the non-structural protein p80/p125 in cells infected with different pestiviruses. The Journal of general virology 48 1309861
2002 Low Mr phosphotyrosine protein phosphatase associates and dephosphorylates p125 focal adhesion kinase, interfering with cell motility and spreading. The Journal of biological chemistry 43 12055185
2000 Integrin-independent tyrosine phosphorylation of p125(fak) in human platelets stimulated by collagen. The Journal of biological chemistry 36 11110790
1999 Hypoxia induces activation and subcellular translocation of focal adhesion kinase (p125(FAK)) in cultured rat cardiac myocytes. Biochemical and biophysical research communications 35 10448107
2006 Basic fibroblast growth factor promotes melanocyte migration via increased expression of p125(FAK) on melanocytes. Acta dermato-venereologica 34 17106595
1998 Are tyrosine phosphorylation of p125(FAK) and paxillin or the small GTP binding protein, rho, needed for CCK-stimulated pancreatic amylase secretion? Biochimica et biophysica acta 31 9739170
2001 Calyculin-A induces focal adhesion assembly and tyrosine phosphorylation of p125(Fak), p130(Cas), and paxillin in Swiss 3T3 cells. Journal of cellular physiology 30 11382927
2000 Determination of functional regions of p125, a novel mammalian Sec23p-interacting protein. Biochemical and biophysical research communications 29 11112430
1995 Comparison of the p125 coding region of bovine viral diarrhea viruses. Veterinary microbiology 26 7653028
2004 Distinct pools of proliferating cell nuclear antigen associated to DNA replication sites interact with the p125 subunit of DNA polymerase delta or DNA ligase I. Experimental cell research 23 14729473
1996 Glucose-induced tyrosine phosphorylation of p125 in beta cells and pancreatic islets. A novel proximal signal in insulin secretion. The Journal of biological chemistry 23 8798659
2011 p125/Sec23-interacting protein (Sec23ip) is required for spermiogenesis. FEBS letters 22 21640725
1998 Characterization of the p125 subunit of human DNA polymerase delta and its deletion mutants. Interaction with cyclin-dependent kinase-cyclins. The Journal of biological chemistry 22 9545286
1998 Pervanadate stimulates amylase release and protein tyrosine phosphorylation of paxillin and p125(FAK) in differentiated AR4-2J pancreatic acinar cells. The Journal of biological chemistry 21 9632700
2016 p53 inhibits the expression of p125 and the methylation of POLD1 gene promoter by downregulating the Sp1-induced DNMT1 activities in breast cancer. OncoTargets and therapy 20 27022290
2011 Significance of DNA polymerase delta catalytic subunit p125 induced by mutant p53 in the invasive potential of human hepatocellular carcinoma. Oncology 19 21372597
1993 Identification of p125, a component of a group of 120-kDa proteins that are phosphorylated on tyrosine residues in response to bradykinin and bombesin stimulation, in anti-ras-GTPase-activating protein immunoprecipitates of Swiss 3T3 cells. The Journal of biological chemistry 19 7681835
2021 Inhibition of Vasculogenic Mimicry and Angiogenesis by an Anti-EGFR IgG1-Human Endostatin-P125A Fusion Protein Reduces Triple Negative Breast Cancer Metastases. Cells 18 34831127
1995 Endothelin-1 stimulates tyrosine phosphorylation of p125 focal adhesion kinase in mesangial cells. Journal of the American Society of Nephrology : JASN 18 8589330
1999 Low density lipoprotein phosphorylates the focal adhesion-associated kinase p125(FAK) in human platelets independent of integrin alphaIIb beta3. The Journal of biological chemistry 17 9867854
1997 Decrease in the amount of focal adhesion kinase (p125(FAK)) in interleukin-1beta-stimulated human umbilical vein endothelial cells by binding of human monocytic cell lines. The Journal of biological chemistry 15 9252385
2024 Sec23IP recruits VPS13B/COH1 to ER exit site-Golgi interface for tubular ERGIC formation. The Journal of cell biology 14 39352497
2000 Tyrosine phosphorylation of p125(Fak), p130(Cas), and paxillin does not require extracellular signal-regulated kinase activation in Swiss 3T3 cells stimulated by bombesin or platelet-derived growth factor. Journal of cellular physiology 13 10737896
2000 Nitric oxide stimulates tyrosine phosphorylation of p125(FAK) and paxillin in rat pancreatic acini. Biochemical and biophysical research communications 13 10924330
2010 AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer. Gene therapy 12 20844568
1999 Regulation of the actin cytoskeleton by p125 focal adhesion kinase in rat pancreatic acinar cells. Digestion 12 10095157
1999 Growth hormone stimulates tyrosine phosphorylation of focal adhesion kinase (p125(FAK)) and actin stress fiber formation in human osteoblast-like cells, Saos2. Biochemical and biophysical research communications 12 10486260
1999 Adhesion to fibronectin promotes the activation of the p125(FAK)/Zap-70complex in human T cells. Immunology 12 10594689
2011 Inhibition of ovarian cancer by RGD-P125A-endostatin-Fc fusion proteins. International journal of cancer 11 21225621
2000 A role for phosphoinositides in tyrosine phosphorylation of p125 focal adhesion kinase in rat pancreatic acini. Cellular signalling 10 10704824
1991 Bovine viral diarrhea virus proteins: relatedness of p175 with p80 and p125 and evidence of glycoprotein processing. Canadian journal of microbiology 9 1663821
2022 RNA-sequencing of myxoinflammatory fibroblastic sarcomas reveals a novel SND1::BRAF fusion and 3 different molecular aberrations with the potential to upregulate the TEAD1 gene including SEC23IP::VGLL3 and TEAD1::MRTFB gene fusions. Virchows Archiv : an international journal of pathology 8 35776191
2000 Expression of focal adhesion kinase (p125 FAK) and proline-rich tyrosine kinase 2 (PYK2/CAKb) in cerebral metastases, correlation with VEGF-R-, ecNOS III-labelling and morphometric data. Anticancer research 8 10928051
2000 Interaction of the retinoblastoma protein (pRb) with the catalytic subunit of DNA polymerase delta (p125). Oncogene 8 11114723
1999 Platelet-activating factor stimulation of p125(FAK) and p130(Cas) tyrosine phosphorylation in brain. Brain research 8 10415383
2020 Identification of Sec23ip, Part of 14-3-3γ Protein Network, as a Regulator of Acute Steroidogenesis in MA-10 Leydig Cells. Endocrinology 7 31875919
1989 An immunocytochemical study of the proliferating cell nuclear matrix antigen p125/6.5 during rat spermatogenesis. Journal of cell science 5 2515195
2024 Antibody-Drug Conjugate αEGFR-E-P125A Reduces Triple-negative Breast Cancer Vasculogenic Mimicry, Motility, and Metastasis through Inhibition of EGFR, Integrin, and FAK/STAT3 Signaling. Cancer research communications 4 38315147
1996 Tyrosine phosphorylation and subcellular redistribution of p125 ras guanosine triphosphatase-activating protein in human neutrophils stimulated with FMLP. FEBS letters 4 8925892
2025 p125A (Sec23ip) couples COPII coat assembly with donor-acceptor membrane organization to facilitate tunnel-based traffic. bioRxiv : the preprint server for biology 3 40463098

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