Affinage

RIN2

Ras and Rab interactor 2 · UniProt Q8WYP3

Length
895 aa
Mass
100.2 kDa
Annotated
2026-06-10
13 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RIN2 is a Rab5 guanine nucleotide exchange factor that couples Ras-family GTPase signaling to early endocytic trafficking, governing receptor internalization and matrix homeostasis (PMID:16423831, PMID:22825554). Containing both a Vps9p-like GEF domain and Ras-association domains, RIN2 acts downstream of activated Ras: HGF-stimulated Ras binds and activates RIN2 to catalyze GDP-to-GTP exchange on Rab5, driving endocytosis of E-cadherin from adherens junctions, a step dependent on its GEF activity (PMID:16423831). In endothelial cells, binding of R-Ras-GTP switches RIN2 from a Rab5 GEF into a Rab5-GTP adaptor that selectively internalizes ligand-bound active β1 integrins and translocates R-Ras to early endosomes, where the R-Ras/RIN2/Rab5 module activates Rac1 through TIAM1 to promote cell adhesion and angiogenesis (PMID:22825554). Loss-of-function frameshift mutations in humans cause depletion of RIN2 and a connective tissue disorder marked by paucity of dermal microfibrils, fibulin-5 deficiency, and abnormal collagen fibril and secretory organelle morphology, establishing RIN2-dependent trafficking as required for normal elastic and connective tissue matrix assembly (PMID:19631308, PMID:20424861).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2006 High

    Established RIN2's core molecular activity by showing it is a Ras-activated Rab5 GEF that drives E-cadherin endocytosis, defining how a Ras signal is converted into an endocytic event.

    Evidence Cell-free endocytosis assay with adherens-junction-enriched liver fractions plus GEF-dead RIN2 constructs in MDCK cells

    PMID:16423831

    Open questions at the time
    • Did not address whether RIN2 acts on cargoes beyond E-cadherin
    • Physiological signals other than HGF/Ras that engage RIN2 not defined
  2. 2012 High

    Resolved how RIN2 function is rewired by a specific Ras isoform, showing R-Ras-GTP converts it from a GEF to a Rab5-GTP adaptor that selectively traffics active β1 integrins and activates Rac1 via TIAM1.

    Evidence Reciprocal Co-IP, GTPase-state-specific binding assays, integrin endocytosis and Rac1 activity assays, confocal localization in endothelial cells

    PMID:22825554

    Open questions at the time
    • Structural basis of the GEF-to-adaptor switch unresolved
    • How RIN2 discriminates between H-Ras and R-Ras inputs in vivo not defined
  3. 2009 Medium

    Connected RIN2 loss to human disease, showing frameshift mutations deplete RIN2 and cause microfibril paucity and fibulin-5 deficiency, linking endocytic trafficking to elastic matrix homeostasis.

    Evidence Human genetic mapping, homozygous frameshift identification, skin biopsy immunostaining and electron microscopy

    PMID:19631308

    Open questions at the time
    • Single family/lab
    • Mechanistic link between Rab5 GEF activity and fibulin-5/microfibril assembly not established
  4. 2010 Medium

    Independently confirmed RIN2's matrix role with a distinct mutation, tying RIN2 loss to abnormal collagen fibrils and dilated ER/abnormal Golgi in fibroblasts.

    Evidence Molecular analysis of a 2-bp frameshift deletion causing NMD, electron microscopy of skin and fibroblasts

    PMID:20424861

    Open questions at the time
    • Single lab
    • How RIN2 loss produces ER/Golgi ultrastructural defects not mechanistically traced
  5. 2022 Low

    Reported a RIN2::BRAF fusion in pilocytic astrocytoma, raising the possibility that RIN2-derived dimerization domains drive oncogenic kinase activation.

    Evidence Genomic fusion transcript identification and structural domain inference

    PMID:36520196

    Open questions at the time
    • Structural inference only; no functional or biochemical validation of fusion protein activity
    • Contribution of RIN2 sequence to BRAF activation untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RIN2's two operating modes are dynamically partitioned and what full cargo repertoire and matrix-assembly pathway connect its trafficking activity to fibulin-5/collagen homeostasis remain unresolved.
  • No structural model of the GEF-to-adaptor switch
  • Mechanistic chain from Rab5-dependent trafficking to elastic/collagen matrix assembly undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
CDH1HRASITGB1RAB5RRASTIAM1
Complex memberships
R-Ras/RIN2/Rab5 module

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 RIN2 acts as a Rab5 GEF downstream of Ras: HGF activates Ras, which binds RIN2 (a protein containing Vps9p-like GEF and Ras-association domains), activating it to exchange GDP for GTP on Rab5, thereby inducing endocytosis of E-cadherin at adherens junctions. RIN2's GEF activity toward Rab5 is required for this process, demonstrated by a cell-free endocytosis assay with AJ-enriched liver fractions and dominant-negative/GEF-dead constructs in MDCK cells. Cell-free endocytosis assay (AJ-enriched rat liver fractions), loss-of-function with GEF-dead RIN2 constructs in MDCK cells, localization at cell-cell adhesion sites The Journal of biological chemistry High 16423831
2012 In endothelial cells, R-Ras-GTP binds RIN2 and converts it from a Rab5 GEF to an adaptor that preferentially binds Rab5-GTP, promoting selective endocytosis of ligand-bound/active β1 integrins and translocating R-Ras to early endosomes where the R-Ras/RIN2/Rab5 module activates Rac1 via TIAM1, driving cell adhesion and angiogenesis. Co-immunoprecipitation, GTPase binding assays, dominant-negative and constitutively-active mutants, integrin endocytosis assays, Rac1 activity assays, TIAM1 interaction studies, localization by confocal microscopy Cell research High 22825554
2009 Loss-of-function frameshift mutations in RIN2 (causing decreased RIN2 expression) result in paucity of dermal microfibrils and deficiency of fibulin-5, establishing that RIN2-mediated endocytic trafficking is required for normal elastic tissue/extracellular matrix homeogenesis in human skin. Human genetic mapping, identification of homozygous frameshift mutation, skin biopsy showing paucity of microfibrils and fibulin-5 deficiency by immunostaining/electron microscopy American journal of human genetics Medium 19631308
2010 A distinct homozygous 2-bp frameshift deletion in RIN2 (c.1914_1915delGC) causes nonsense-mediated mRNA decay and loss of RIN2, and is associated with abnormal collagen fibril morphology in skin and ultrastructural abnormalities in fibroblasts (dilated ER, abnormal Golgi), confirming that RIN2-dependent trafficking is required for normal connective tissue matrix assembly. Molecular analysis of RIN2 mutation, ultrastructural analysis of skin (electron microscopy), fibroblast morphology Human genetics Medium 20424861
2022 A RIN2::BRAF gene fusion found in pilocytic astrocytoma encodes a chimeric protein retaining RIN2's SH2 dimerization domain fused to the intact BRAF kinase domain, consistent with oncogenic kinase activation via constitutive dimerization. Genomic sequencing/fusion transcript identification, structural domain analysis of fusion protein Virchows Archiv Low 36520196

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. Cell research 98 22825554
2006 Involvement of the Ras-Ras-activated Rab5 guanine nucleotide exchange factor RIN2-Rab5 pathway in the hepatocyte growth factor-induced endocytosis of E-cadherin. The Journal of biological chemistry 60 16423831
2009 RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome. American journal of human genetics 59 19631308
2010 The RIN2 syndrome: a new autosomal recessive connective tissue disorder caused by deficiency of Ras and Rab interactor 2 (RIN2). Human genetics 38 20424861
2022 Compassionate open-label use of rituximab following a randomised clinical trial against neuromyelitis optica (RIN-2 study): B cell monitoring-based administration. Multiple sclerosis and related disorders 21 35287025
2021 Novel 61-bp Indel of RIN2 Is Associated With Fat and Hatching Weight Traits in Chickens. Frontiers in genetics 11 34276778
2016 RIN2 syndrome: Expanding the clinical phenotype. American journal of medical genetics. Part A 8 27277385
2013 Newly described clinical features in two siblings with MACS syndrome and a novel mutation in RIN2. American journal of medical genetics. Part A 8 24449201
2023 NAA20 recruits Rin2 and promotes triple-negative breast cancer progression by regulating Rab5A-mediated activation of EGFR signaling. Cellular signalling 6 37827343
2019 Leukoencephalopathy in RIN2 syndrome: Novel mutation and expansion of clinical spectrum. European journal of medical genetics 4 30769224
2019 RIN2 and BBS7 variants as cause of a coincidental syndrome. European journal of medical genetics 3 31521835
2022 Rare adult pilocytic astrocytoma of the septum pellucidum with novel RIN2::BRAF fusion. Virchows Archiv : an international journal of pathology 1 36520196
2026 RIN2 reveals a novel role in regulating proliferation and early adipogenesis of chicken preadipocytes. Frontiers in veterinary science 0 42125753

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