Affinage

RABEP2

Rab GTPase-binding effector protein 2 · UniProt Q9H5N1

Length
569 aa
Mass
63.5 kDa
Annotated
2026-06-10
100 papers in source corpus 1 papers cited in narrative 1 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 2/2 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RABEP2 is a Rab-effector protein that governs the endosomal trafficking of VEGFR2 in endothelial cells to sustain VEGF signaling (PMID:29425100). It binds the small GTPase Rab4 and directs VEGFR2 recycling to the cell surface; in its absence VEGFR2 is retained in Rab5-positive sorting endosomes, where increased exposure to the phosphotyrosine phosphatase PTP1b dampens signaling, and is additionally diverted to Rab7-positive endosomes destined for lysosomal degradation (PMID:29425100). Beyond this single characterization of its role in VEGFR2 trafficking, no further mechanistic detail has been established in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 2018 Medium

    Whether and how a dedicated effector controls VEGFR2 fate after endocytosis was unresolved; this work established RABEP2 as a Rab4-binding effector that routes VEGFR2 toward recycling and away from phosphatase-mediated inactivation and lysosomal degradation.

    Evidence Co-immunoprecipitation/pulldown, high-resolution microscopy, endosomal fractionation, and RABEP2 loss-of-function with VEGFR2 surface-expression, signaling, and degradation readouts in endothelial cells

    PMID:29425100

    Open questions at the time
    • Single-lab study without independent replication
    • Structural basis of the RABEP2–Rab4 interaction and the recycling step not defined
    • Whether RABEP2 acts on cargoes other than VEGFR2 not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown whether RABEP2 functions in non-endothelial cell types or regulates additional receptor cargoes, and the molecular determinants of its Rab4-dependent recycling activity are uncharacterized.
  • No structural model of RABEP2 or its Rab4 complex
  • No in vivo or organismal phenotype data captured
  • Mechanism by which RABEP2 selects recycling versus degradative routes unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 1
Localization
GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
KDRRAB4

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 RABEP2 interacts with the small GTPase Rab4 and regulates VEGFR2 endosomal trafficking to maintain cell-surface expression of VEGFR2 and VEGF signaling. Loss of RABEP2 caused prolonged retention of VEGFR2 in Rab5-positive sorting endosomes, increasing VEGFR2 exposure to phosphotyrosine phosphatase 1b (PTP1b) and diminishing VEGFR2 signaling. Loss of RABEP2 also increased VEGFR2 degradation by diverting it to Rab7-positive endosomes destined for the lysosome. High-resolution microscopy, biochemical assays (co-immunoprecipitation/pulldown), endosomal fractionation, loss-of-function (RABEP2 knockdown/knockout) with defined phenotypic readouts (VEGFR2 surface expression, signaling, degradation) The Journal of biological chemistry Medium 29425100

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 fra-1: a serum-inducible, cellular immediate-early gene that encodes a fos-related antigen. Molecular and cellular biology 573 3133553
1989 Glutamate receptor agonists increase the expression of Fos, Fra, and AP-1 DNA binding activity in the mammalian brain. Journal of neuroscience research 338 2553994
1990 Isolation and characterization of fra-2, an additional member of the fos gene family. Proceedings of the National Academy of Sciences of the United States of America 310 2110368
1993 The NFAT-1 DNA binding complex in activated T cells contains Fra-1 and JunB. Molecular and cellular biology 221 8441422
1991 Difference in transcriptional regulatory function between c-Fos and Fra-2. Nucleic acids research 209 1945831
2012 MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1. Oncogene 191 23001043
2010 Fra-1 protooncogene regulates IL-6 expression in macrophages and promotes the generation of M2d macrophages. Cell research 183 20386569
1998 Fra-1 induces morphological transformation and increases in vitro invasiveness and motility of epithelioid adenocarcinoma cells. Molecular and cellular biology 170 9819396
2003 Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. Cancer research 162 12727841
2013 MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene. Oncogene 161 23831570
1995 Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron. Molecular and cellular biology 160 7791782
2004 The Fos-related antigen Fra-1 is an activator of bone matrix formation. The EMBO journal 159 15229648
2008 Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 153 18548006
2013 Identification of a pharmacologically tractable Fra-1/ADORA2B axis promoting breast cancer metastasis. Proceedings of the National Academy of Sciences of the United States of America 145 23483055
1994 Regulation of Fra-1 and Fra-2 phosphorylation differs during the cell cycle of fibroblasts and phosphorylation in vitro by MAP kinase affects DNA binding activity. Oncogene 138 8058317
2014 Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression. Cell death and differentiation 131 25301070
2000 Fra-1 replaces c-Fos-dependent functions in mice. Genes & development 129 11069886
2012 Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease. SpringerPlus 122 23961352
2010 Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production. The Journal of cell biology 119 20837772
2007 Deciphering AP-1 function in tumorigenesis: fra-ternizing on target promoters. Cell cycle (Georgetown, Tex.) 117 17957143
2006 Fra-1 a target for cancer prevention or intervention. Gene 109 16784822
2002 Transactivation of Fra-1 and consequent activation of AP-1 occur extracellular signal-regulated kinase dependently. Molecular and cellular biology 106 11756554
1997 Enhanced CREB phosphorylation and changes in c-Fos and FRA expression in striatum accompany amphetamine sensitization. Brain research 105 9070635
2019 Fra-2-expressing macrophages promote lung fibrosis in mice. The Journal of clinical investigation 95 31135379
1996 Transcription factor AP-1, and the role of Fra-2. Immunology and cell biology 94 8723999
2010 The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis and rheumatism 93 20039427
2013 Expression of folate receptor-α (FRA) in gynecologic malignancies and its relationship to the tumor type. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists 90 23518909
2011 Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene 90 21822309
2003 Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway. Genes to cells : devoted to molecular & cellular mechanisms 90 12622723
2016 SIRT1 promotes epithelial-mesenchymal transition and metastasis in colorectal cancer by regulating Fra-1 expression. Cancer letters 84 26975631
2002 Mesothelial cell transformation requires increased AP-1 binding activity and ERK-dependent Fra-1 expression. Cancer research 81 12414630
2017 Linear Integration of ERK Activity Predominates over Persistence Detection in Fra-1 Regulation. Cell systems 75 29199017
2004 An extracellular signal-regulated kinase 1- and 2-dependent program of chromatin trafficking of c-Fos and Fra-1 is required for cyclin D1 expression during cell cycle reentry. Molecular and cellular biology 75 15143165
2007 Fra-1 and Stat3 synergistically regulate activation of human MMP-9 gene. Molecular immunology 71 17572495
2019 Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis. The Journal of clinical investigation 70 30990796
2017 High expression of Collagen Triple Helix Repeat Containing 1 (CTHRC1) facilitates progression of oesophageal squamous cell carcinoma through MAPK/MEK/ERK/FRA-1 activation. Journal of experimental & clinical cancer research : CR 65 28645305
1993 Selective induction of Fos and FRA immunoreactivity within the mesolimbic and mesostriatal dopamine terminal fields. Synapse (New York, N.Y.) 65 8497810
2013 Folate receptor alpha (FRA) expression remains unchanged in epithelial ovarian and endometrial cancer after chemotherapy. Gynecologic oncology 64 23558051
2014 FRA-1 as a driver of tumour heterogeneity: a nexus between oncogenes and embryonic signalling pathways in cancer. Oncogene 63 25381818
2007 Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia. Oncogene 63 18071306
2020 The nuclear oncoprotein Fra-1: a transcription factor knocking on therapeutic applications' door. Oncogene 62 32385348
2007 FRA-1 proto-oncogene induces lung epithelial cell invasion and anchorage-independent growth in vitro, but is insufficient to promote tumor growth in vivo. Cancer research 58 17616677
2007 HGF mediates cell proliferation of human mesothelioma cells through a PI3K/MEK5/Fra-1 pathway. American journal of respiratory cell and molecular biology 58 17872495
2014 Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia. Cell death and differentiation 56 24464219
2013 SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma. Blood 56 23482931
2019 Transcription factor Fra-2 and its emerging role in matrix deposition, proliferation and inflammation in chronic lung diseases. Cellular signalling 55 31473307
2012 The PKCθ pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells. Oncogene 55 22286759
2006 The duration of ERK1/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1. Cellular signalling 54 17052890
1997 Phosphorylation and high level expression of Fra-2 in v-src transformed cells: a pathway of activation of endogenous AP-1. Oncogene 54 9188858
2022 The Fra-1/AP-1 Oncoprotein: From the "Undruggable" Transcription Factor to Therapeutic Targeting. Cancers 51 35326630
2018 The Rab-effector protein RABEP2 regulates endosomal trafficking to mediate vascular endothelial growth factor receptor-2 (VEGFR2)-dependent signaling. The Journal of biological chemistry 50 29425100
2001 Tissue-specific transgenic knockdown of Fos-related antigen 2 (Fra-2) expression mediated by dominant negative Fra-2. Molecular and cellular biology 50 11340164
2004 Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. American journal of respiratory cell and molecular biology 49 15528491
2013 Osteoblast-specific expression of Fra-2/AP-1 controls adiponectin and osteocalcin expression and affects metabolism. Journal of cell science 47 24046454
2007 Restraint-induced fra-2 and c-fos expression in the rat forebrain: relationship to stress duration. Neuroscience 47 17936518
2017 MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells. Oncogenesis 46 28604765
2015 Fra-1 is upregulated in gastric cancer tissues and affects the PI3K/Akt and p53 signaling pathway in gastric cancer. International journal of oncology 46 26330014
2011 Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells. Biochimica et biophysica acta 46 21640141
2007 FRA-1 protein overexpression is a feature of hyperplastic and neoplastic breast disorders. BMC cancer 45 17254320
1999 Fra-2-positive autoregulatory loop triggered by mitogen-activated protein kinase (MAPK) and Fra-2 phosphorylation sites by MAPK. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 45 10359014
1994 Cloning and characterisation of the mouse fra-2 gene. Oncogene 45 7936655
2014 Terminal epidermal differentiation is regulated by the interaction of Fra-2/AP-1 with Ezh2 and ERK1/2. Genes & development 44 25547114
2011 Elevated Fra-1 expression causes severe lipodystrophy. Journal of cell science 44 21486951
2000 FRA-1 expression in hyperplastic and neoplastic thyroid diseases. Clinical cancer research : an official journal of the American Association for Cancer Research 44 11106247
2016 The Fra-1-miR-134-SDS22 feedback loop amplifies ERK/JNK signaling and reduces chemosensitivity in ovarian cancer cells. Cell death & disease 43 27685628
2007 Role of Fra-2 in breast cancer: influence on tumor cell invasion and motility. Breast cancer research and treatment 43 17393299
2007 Ubiquitin-independent- versus ubiquitin-dependent proteasomal degradation of the c-Fos and Fra-1 transcription factors: is there a unique answer? Biochimie 43 17825471
2015 Fra-1 is upregulated in lung cancer tissues and inhibits the apoptosis of lung cancer cells by the P53 signaling pathway. Oncology reports 42 26549498
2020 Ubiquitin-Specific Protease 21 Promotes Colorectal Cancer Metastasis by Acting as a Fra-1 Deubiquitinase. Cancers 41 31947604
2012 Fra-1 promotes breast cancer chemosensitivity by driving cancer stem cells from dormancy. Cancer research 39 22586064
2008 A Fra-1-dependent, matrix metalloproteinase driven EGFR activation promotes human lung epithelial cell motility and invasion. Journal of cellular physiology 39 18288638
2005 Cloning, expression, and clinical significance of the major allergen from ash pollen, Fra e 1. The Journal of allergy and clinical immunology 39 15696094
1996 Changes in the expression of transcription factors ATF-2 and Fra-2 after axotomy and during regeneration in rat retinal ganglion cells. Brain research. Molecular brain research 39 8883934
2010 Fra-2 mediates oxygen-sensitive induction of transforming growth factor beta in cardiac fibroblasts. Cardiovascular research 38 20427335
2013 Effect of estrogen and tamoxifen on the expression pattern of AP-1 factors in MCF-7 cells: role of c-Jun, c-Fos, and Fra-1 in cell cycle regulation. Molecular and cellular biochemistry 37 23625206
2012 Intermittent hypoxia and systemic leptin administration induces pSTAT3 and Fos/Fra-1 in the carotid body. Brain research 37 22364734
2006 A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression. The Journal of biological chemistry 37 16490785
2017 Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription. The Journal of experimental medicine 36 28566276
2003 DEP-induced fra-1 expression correlates with a distinct activation of AP-1-dependent gene transcription in the lung. American journal of physiology. Lung cellular and molecular physiology 36 14565943
2023 FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer. International journal of molecular sciences 35 37176013
1995 Cyclic AMP stimulates a JunD/Fra-2 AP-1 complex and inhibits the proliferation of interleukin-6-dependent cell lines. Oncogene 35 7566966
1997 Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis). Oncogene 34 9294610
2012 Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo. PloS one 33 22911824
2001 Cholesterol sulfate stimulates involucrin transcription in keratinocytes by increasing Fra-1, Fra-2, and Jun D. Journal of lipid research 33 11254751
2001 Parathyroid hormone stimulates fra-2 expression in osteoblastic cells in vitro and in vivo. Endocrinology 33 11316763
2018 Integrin-uPAR signaling leads to FRA-1 phosphorylation and enhanced breast cancer invasion. Breast cancer research : BCR 32 29382358
2005 MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability. Oncogene 30 15558021
2002 Dual role for mitogen-activated protein kinase (Erk) in insulin-dependent regulation of Fra-1 (fos-related antigen-1) transcription and phosphorylation. The Biochemical journal 30 12197835
2005 Induction of the RelB NF-kappaB subunit by the cytomegalovirus IE1 protein is mediated via Jun kinase and c-Jun/Fra-2 AP-1 complexes. Journal of virology 29 15596805
2020 Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway. Frontiers in cell and developmental biology 27 33102485
2008 ERK signaling regulates tumor promoter induced c-Jun recruitment at the Fra-1 promoter. Biochemical and biophysical research communications 27 18435914
2007 Simultaneous generation of fra-2 conditional and fra-2 knock-out mice. Genesis (New York, N.Y. : 2000) 27 17607691
2024 Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc. Proceedings of the National Academy of Sciences of the United States of America 26 38657045
2022 NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation. Oncogene 26 34992218
2018 MiR-124-3p suppresses glioma aggressiveness via targeting of Fra-2. Pathology, research and practice 26 30243808
1990 Inhibition of PC-12 cell differentiation by the immediate early gene fra-1. Oncogene 26 2178237
2022 The Fra-1: Novel role in regulating extensive immune cell states and affecting inflammatory diseases. Frontiers in immunology 25 36032067
1991 Transcription of fra-2 mRNA and phosphorylation of Fra-2 protein are stimulated by serum. Biochemical and biophysical research communications 25 1899576
2016 HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells. Oncotarget 24 26734995
2011 Transcription factor Fra-1 induces cholangitis and liver fibrosis. Hepatology (Baltimore, Md.) 24 21480331

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