Affinage

RAP2C

Ras-related protein Rap-2c · UniProt Q9Y3L5

Length
183 aa
Mass
20.7 kDa
Annotated
2026-04-28
16 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAP2C is a plasma membrane-associated small GTPase of the Rap2 subfamily that integrates upstream signals from junctional complexes, GPCRs, and B cell receptors to regulate cytoskeletal dynamics, Hippo–YAP signaling, MAPK cascades, and mitochondrial morphology. At epithelial tight junctions, RAP2C is activated by a JAM-A/ZO-2/afadin/PDZ-GEF1 complex to control apical actomyosin contraction and barrier permeability through RhoA and nonmuscle myosin phosphorylation (PMID:23885123). In fibroblasts, Gαs-coupled GPCR signaling activates RAP2C via EPAC1/2, which engages MAP4K7 to phosphorylate LATS1/2 and exclude YAP/TAZ from the nucleus, thereby suppressing proliferation and extracellular matrix production (PMID:34046891). RAP2C also associates with the mitochondrial fission regulator DRP1, promoting DRP1 S637 phosphorylation and mitochondrial fusion to enhance oxidative phosphorylation (PMID:36214632), and activates MAPK signaling (ERK, JNK, P38) through MAP4K family kinases in multiple cell types (PMID:31541458, PMID:34676879).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2005 High

    Establishing RAP2C as a bona fide GTPase defined a new Rap2 subfamily member and showed it differs from RAP2B in nucleotide handling and reaches the plasma membrane via its CAAX motif.

    Evidence In vitro nucleotide binding assays with purified recombinant protein and subcellular localization in eukaryotic cells

    PMID:16213650

    Open questions at the time
    • No GTPase-activating protein (GAP) or guanine nucleotide exchange factor (GEF) identified at this stage
    • Functional role in intact cells unknown
    • No comparison of isoform-specific signaling outputs
  2. 2007 Medium

    Demonstrating that RAP2C overexpression activates serum response element (SRE) transcription provided the first link between this GTPase and gene regulation, though the pathway was undefined.

    Evidence Luciferase reporter assays in HEK293T cells with RAP2C overexpression

    PMID:17447155

    Open questions at the time
    • Overexpression-only system without endogenous protein validation
    • Downstream effectors mediating SRE activation not identified
    • No loss-of-function data
  3. 2013 High

    Placing RAP2C downstream of a JAM-A/ZO-2/afadin/PDZ-GEF1 junctional complex that regulates RhoA-dependent actomyosin contraction provided the first complete signaling axis and physiological context for RAP2C in epithelial barrier maintenance.

    Evidence Reciprocal co-immunoprecipitation, siRNA epistasis, paracellular permeability assays, JAM-A-deficient mice, RhoA activity and myosin phosphorylation readouts

    PMID:23885123

    Open questions at the time
    • Direct GEF activity of PDZ-GEF1 on RAP2C not reconstituted in vitro
    • How RAP2C activates RhoA mechanistically is unclear
    • Relative contributions of Rap2 isoforms in vivo not resolved
  4. 2018 Medium

    Identifying RAP2C as the sole Rap2 isoform in A20 B cells required for BCR-induced MTOC reorientation and actin remodeling extended its cytoskeletal control function to immune cell polarity.

    Evidence siRNA knockdown of Rap2c in B cells with live imaging of MTOC polarization and F-actin dynamics on antigen-coated surfaces

    PMID:29457987

    Open questions at the time
    • Effector kinase or scaffold linking RAP2C to MTOC reorientation machinery not identified
    • Single cell line (A20); generalizability to primary B cells untested
    • Upstream GEF activating RAP2C upon BCR engagement unknown
  5. 2019 Medium

    Multiple studies converged on RAP2C as a positive regulator of MAPK (ERK/JNK/P38) signaling in cancer and disease models, with its expression controlled by miRNAs (miR-188-5p, miR-195, miR-136-5p, miR-200c-3p), establishing RAP2C as a MAPK-activating node subject to extensive post-transcriptional regulation.

    Evidence Dual-luciferase 3′UTR reporter assays confirming miRNA–RAP2C interactions; knockdown and overexpression with MAPK phosphorylation readouts in breast cancer, SCLC, LSCC, and nucleus pulposus cells

    PMID:31541458 PMID:32014687 PMID:33302819 PMID:34676879

    Open questions at the time
    • Direct biochemical mechanism by which RAP2C activates MAPK kinases not resolved
    • Isoform specificity (RAP2A/B vs C) in MAPK activation not tested
    • miRNA studies are individually single-lab without independent replication
  6. 2021 High

    Demonstrating that EPAC1/2→RAP2C→MAP4K7→LATS1/2 signaling excludes YAP/TAZ from the nucleus in fibroblasts connected RAP2C to the Hippo pathway and explained how Gαs-coupled GPCRs suppress fibrotic responses.

    Evidence Sequential siRNA knockdowns of EPAC1/2, RAP2C, and MAP4K7 in primary human lung fibroblasts with YAP/TAZ localization imaging, proliferation, contraction, and ECM assays

    PMID:34046891

    Open questions at the time
    • Whether RAP2C directly binds and activates MAP4K7 or acts through an intermediate is unknown
    • Structural basis of RAP2C–MAP4K7 interaction not determined
    • In vivo relevance in fibrotic disease models not shown
  7. 2022 High

    Discovering that RAP2C associates with DRP1 and promotes DRP1 S637 phosphorylation to drive mitochondrial fusion and oxidative phosphorylation revealed a non-canonical mitochondrial function for this GTPase, with therapeutic relevance to MAPK-inhibitor resistance in melanoma.

    Evidence Reciprocal co-immunoprecipitation of RAP2C–DRP1, siRNA knockdown of LENOX and RAP2C, DRP1 phosphorylation western blot, mitochondrial morphology imaging, metabolic assays, in vivo melanoma models

    PMID:36214632

    Open questions at the time
    • Whether RAP2C directly phosphorylates DRP1 or recruits a kinase is unresolved
    • Role of GTP-bound vs GDP-bound state in DRP1 interaction not tested
    • Generalizability beyond melanoma not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for RAP2C effector selectivity (MAP4K4/MAP4K7, DRP1, RhoA regulators), whether its GTPase cycle is differentially controlled by specific GAPs in different tissues, and how its mitochondrial versus plasma membrane pools are partitioned.
  • No crystal or cryo-EM structure of RAP2C in complex with any effector
  • GAP specificity for RAP2C not characterized
  • Conditional knockout mouse models are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0003924 GTPase activity 1
Localization
GO:0005739 mitochondrion 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1500931 Cell-Cell communication 1 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
DRP1EPAC1EPAC2JAM-AMAP4K4MAP4K7PDZ-GEF1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Rap2C is a new member of the Rap2 subfamily of small GTPases that binds GTP in a Mg2+-dependent manner, with slower GDP release and lower relative GTP affinity compared to Rap2B. When expressed in eukaryotic cells, Rap2C localizes to the plasma membrane via its C-terminal CAAX motif. In vitro nucleotide binding assays with recombinant purified protein, eukaryotic cell expression with subcellular localization Biochimie High 16213650
2007 Overexpression of RAP2C in HEK293T cells activates transcriptional activity of the serum response element (SRE), suggesting involvement in SRE-mediated gene transcription. RAP2C protein localizes to the cytoplasm when overexpressed in COS-7 cells. Reporter gene (luciferase) assays, RT-PCR, overexpression in COS-7 and HEK293T cells Molecular biology reports Medium 17447155
2013 JAM-A associates directly with ZO-2 and indirectly with afadin; this complex, together with PDZ-GEF1, activates the small GTPase Rap2c to regulate epithelial barrier function by controlling apical actomyosin contraction via RhoA activity and nonmuscle myosin phosphorylation. Co-immunoprecipitation, siRNA knockdown with paracellular permeability assays, JAM-A-deficient mice, RhoA activity assays, myosin phosphorylation western blot Molecular biology of the cell High 23885123
2018 Rap2c overexpression promotes migration and invasion of osteosarcoma cells by increasing MMP2 activity and phosphorylation of Akt, while decreasing TIMP2; Rap2c knockdown has the opposite effect with no impact on proliferation or apoptosis. Overexpression and siRNA knockdown, Transwell migration/invasion assay, MMP2 activity assay, western blot for pAkt and TIMP2 Oncology letters Medium 29552178
2018 Rap2c is the only Rap2 isoform expressed in A20 B cells and is required for BCR-induced reorientation of the microtubule-organizing center (MTOC) and F-actin remodeling at the antigen contact site. siRNA knockdown of Rap2c, live imaging of MTOC polarization and F-actin remodeling in B cells stimulated on antigen-coated surfaces Small GTPases Medium 29457987
2019 miR-188-5p targets the 3'UTR of Rap2c mRNA (confirmed by dual-luciferase assay), and Rap2c acts as a molecular switch for MAPK signaling to promote proliferation and migration while decreasing apoptosis in breast cancer cells. Dual-luciferase reporter assay, siRNA knockdown, overexpression, CCK-8, flow cytometry, Transwell assay Journal of cellular physiology Medium 31541458
2020 miR-195 binds to Rap2C mRNA (confirmed by luciferase reporter assay) and inhibits Rap2C expression, thereby suppressing MAPK signaling and promoting apoptosis while inhibiting proliferation in small cell lung cancer cells. Luciferase reporter assay, qRT-PCR, western blot, overexpression and knockdown, CCK-8, flow cytometry, subcutaneous mouse model Technology in cancer research & treatment Medium 33302819
2020 circRNA_100290 acts as a sponge for miR-136-5p, relieving miR-136-5p-mediated repression of RAP2C, thereby promoting proliferation, migration, and invasion in laryngeal squamous cell carcinoma cells. Dual-luciferase reporter assay, siRNA knockdown, overexpression, CCK-8, Transwell assay, in vivo xenograft Biomedicine & pharmacotherapy Medium 32014687
2021 In fibroblasts, GPCR agonism activates cAMP effectors EPAC1/2, which activate RAP2C, which in turn activates the serine/threonine kinase MAP4K7, leading to LATS1/2-mediated phosphorylation and nuclear exclusion (inactivation) of YAP/TAZ, reducing fibroblast proliferation, contraction, and extracellular matrix production. siRNA knockdown of EPAC1/2, RAP2C, and MAP4K7 in human lung fibroblasts; YAP/TAZ nuclear localization imaging; fibroblast proliferation, contraction, and ECM assays Journal of cellular physiology High 34046891
2021 RAP2C promotes apoptosis, inflammatory cytokine release, and extracellular matrix degradation in nucleus pulposus cells via activation of ERK signaling; miR-200c-3p targets RAP2C's 3'UTR (confirmed by luciferase assay) to suppress this pathway. Luciferase reporter assay, miRNA mimic/inhibitor transfection, RAP2C knockdown, western blot for ERK signaling, cell apoptosis assay Molecular medicine reports Medium 34676879
2022 The lncRNA LENOX promotes association of RAP2C GTPase with mitochondrial fission regulator DRP1, increasing DRP1 S637 phosphorylation, promoting mitochondrial fusion, and enhancing oxidative phosphorylation in melanoma cells, facilitating resistance to MAPK inhibitors. Co-immunoprecipitation, siRNA knockdown of LENOX and RAP2C, phosphorylation western blot (DRP1 S637), mitochondrial morphology imaging, metabolic assays, in vivo melanoma models Cancer research High 36214632
2024 RAP2C interacts with MAP4K4 (confirmed by co-immunoprecipitation and immunofluorescence), and this interaction is upregulated by hypoxia/reoxygenation; RAP2C overexpression activates the MAPK pathway (JNK, P38, ERK phosphorylation) and promotes cardiomyocyte apoptosis via MAP4K4, while ischemic postconditioning reduces RAP2C–MAP4K4 interaction and cardiomyocyte apoptosis. Co-immunoprecipitation, immunofluorescence co-localization, RAP2C knockdown and overexpression, MAP4K4 knockdown, western blot for phospho-JNK/P38/ERK, apoptosis assay, rat I/R model bioRxivpreprint Medium bio_10.1101_2024.12.04.626922

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function. Molecular biology of the cell 102 23885123
2005 Identification and biochemical characterization of Rap2C, a new member of the Rap family of small GTP-binding proteins. Biochimie 43 16213650
2020 Overexpression of circRNA_100290 promotes the progression of laryngeal squamous cell carcinoma through the miR-136-5p/RAP2C axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 38 32014687
2019 MicroRNA-188-5p promotes apoptosis and inhibits cell proliferation of breast cancer cells via the MAPK signaling pathway by targeting Rap2c. Journal of cellular physiology 38 31541458
2021 Serum long non‑coding RNA NNT‑AS1 protected by exosome is a potential biomarker and functions as an oncogene via the miR‑496/RAP2C axis in colorectal cancer. Molecular medicine reports 33 34132374
2022 The LncRNA LENOX Interacts with RAP2C to Regulate Metabolism and Promote Resistance to MAPK Inhibition in Melanoma. Cancer research 31 36214632
2018 Ras-related protein Rap2c promotes the migration and invasion of human osteosarcoma cells. Oncology letters 22 29552178
2007 Cloning and characterization of the human gene RAP2C, a novel member of Ras family, which activates transcriptional activities of SRE. Molecular biology reports 20 17447155
2021 GPCR-mediated YAP/TAZ inactivation in fibroblasts via EPAC1/2, RAP2C, and MAP4K7. Journal of cellular physiology 18 34046891
2020 microRNA-195 Promotes Small Cell Lung Cancer Cell Apoptosis via Inhibiting Rap2C Protein-Dependent MAPK Signal Transduction. Technology in cancer research & treatment 9 33302819
2021 MicroRNA‑200c‑3p suppresses intervertebral disc degeneration by targeting RAP2C/ERK signaling. Molecular medicine reports 8 34676879
2017 Spinal cord ischemia-reperfusion causes damage of neurocyte by inhibiting RAP2C. Neurological research 8 28714326
2018 The Rap2c GTPase facilitates B cell receptor-induced reorientation of the microtubule-organizing center. Small GTPases 4 29457987
2021 Erratum: Ras-related protein Rap2c promotes the migration and invasion of human osteosarcoma cells. Oncology letters 1 33907572
2025 Stability of G/C DNA Tetraplexes at Physiological pH Formed at the Promoter-UTR Intersection of the RAP2C Gene: Structural Multitude of a G/C Rich Genomic Segment. ACS omega 0 41280817
2025 Multiformity of a G/C Rich Segment at the Promoter-UTR Intersection of RAP2C Gene: Structural Validation by Circular Dichroism. ACS omega 0 41280826