Affinage

GCC2

GRIP and coiled-coil domain-containing protein 2 · UniProt Q8IWJ2

Length
1684 aa
Mass
195.9 kDa
Annotated
2026-06-10
18 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GCC2 (GCC185) is a peripheral membrane coiled-coil tethering protein of the trans-Golgi network (TGN) that coordinates retrograde vesicle capture and Golgi ribbon architecture (PMID:12446665, PMID:21875948). Its C-terminal GRIP domain is necessary and sufficient for targeting to a distinct TGN subcompartment (PMID:12446665), and the protein is recruited and oriented through interactions with small GTPases, binding up to 14 Rab GTPases across multiple sites along its length, including a functionally critical central Rab9-binding site (PMID:18946081). Through this Rab9-effector activity GCC2 mediates recycling of mannose 6-phosphate receptors (MPRs) from late endosomes to the TGN, such that its depletion drives MPR mis-sorting, enhanced MPR degradation, and elevated lysosomal hydrolase secretion (PMID:16885419); the same retrograde route delivers shiga toxin to the Golgi (PMID:17488291). GCC2 separates these activities into discrete domains: a vesicle-tethering domain that directly binds the clathrin adaptor AP-1 to capture MPR-laden, AP-1-decorated transport vesicles, and a separate domain dedicated to maintaining Golgi structure (PMID:21875948). Golgi ribbon integrity is sustained through a GTP-dependent interaction with ARL4A via the CC2 coiled-coil sub-domain, which licenses GCC2 to recruit the microtubule-associated proteins CLASP1 and CLASP2 to the Golgi (PMID:22159419). GCC2 is co-opted in disease contexts: HIV-1 Nef binds GCC2 to disrupt the GCC2–Rab9 interaction and impair retrograde transport (PMID:27105913), and uses GCC2 as a focal scaffold to assemble a multi-protein complex driving MHC-I downregulation (PMID:30953643); chromosomal rearrangement generates a constitutively active GCC2-ALK oncogenic fusion kinase that hyperactivates MAPK, PI3K, and STAT3 signaling and is sensitive to crizotinib (PMID:29290262).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2002 High

    Established where GCC2 acts in the cell and how it is targeted there, defining it as a GRIP-domain TGN protein occupying a distinct subcompartment.

    Evidence Immunofluorescence, immunoelectron microscopy, and truncation constructs in HeLa cells

    PMID:12446665

    Open questions at the time
    • Did not identify the GTPase or lipid partners mediating GRIP-domain recruitment
    • No functional role assigned
  2. 2006 High

    Assigned GCC2 a concrete transport function by showing it is a Rab9 effector required for MPR recycling from late endosomes to the TGN.

    Evidence siRNA depletion, in vitro transport assay, functional rescue, hexosaminidase secretion assay

    PMID:16885419

    Open questions at the time
    • Molecular mechanism of vesicle capture not resolved
    • Did not distinguish tethering from sorting roles
  3. 2007 High

    Broadened GCC2 function to general retrograde endosome-to-TGN transport and revealed a second, separable role in Golgi ribbon organization.

    Evidence siRNA and miRNA depletion in HeLa cells, shiga toxin trafficking and MPR distribution assays

    PMID:17488291

    Open questions at the time
    • Did not determine whether transport and structural defects share a mechanism
    • Cargo selectivity of the retrograde pathway unexplained
  4. 2008 High

    Mapped the GTPase code recruiting and orienting GCC2, identifying Rab6/Arl1 cooperative recruitment at the C-terminus and a dispersed set of Rab-binding sites including a functional Rab9 site.

    Evidence Crystal structure of Rab6–GCC2 RBD, mutagenesis, yeast two-hybrid, biochemical binding, and functional rescue assays

    PMID:18243103 PMID:18946081

    Open questions at the time
    • The Rab6/Arl1 recruitment model was contradicted for endogenous protein
    • Functional significance of most of the 14 Rab interactions undefined
  5. 2009 Medium

    Challenged the Rab6/Arl1 recruitment model by showing endogenous GCC2 Golgi localization is independent of Rab6A/A' and Arl1.

    Evidence Rab6A/A' and Arl1 siRNA depletion, yeast two-hybrid, and colocalization on endogenous protein

    PMID:19703403

    Open questions at the time
    • Negative result from a single lab contradicting prior crystal structure work
    • Did not identify the alternative endogenous recruitment determinant
  6. 2011 High

    Resolved GCC2 into two molecularly distinct activities and identified the direct tethering partner, showing one domain binds AP-1 to capture MPR-laden vesicles while a separate domain maintains Golgi structure.

    Evidence Domain deletion/rescue, AP-1 co-IP, siRNA with vesicle accumulation assay; and ARL4A GTP-dependent co-IP/GST pulldown with CLASP recruitment assay

    PMID:21875948 PMID:22159419

    Open questions at the time
    • How CLASP recruitment maintains ribbon integrity mechanistically unresolved
    • Coupling between AP-1 tethering and Rab9/MPR sorting not detailed
  7. 2019 Medium

    Showed GCC2 is exploited as a viral scaffold, with HIV-1 Nef binding GCC2 to disrupt Rab9 association and assemble a TGN complex driving MHC-I downregulation.

    Evidence Co-IP in Jurkat T and THP-1 cells, siRNA knockdown, confocal microscopy, hexosaminidase and MHC-I flow cytometry

    PMID:27105913 PMID:30953643

    Open questions at the time
    • Single-lab interaction mapping with limited orthogonal validation
    • Stoichiometry and architecture of the Nef-GCC2 complex undefined
  8. 2024 Medium

    Linked GCC2 to cancer cell biology, both as a constitutively active fusion kinase (GCC2-ALK) and as a regulator of EGFR signaling and trafficking when its levels are altered.

    Evidence Ba/F3 IL-3 independence and crizotinib assays for GCC2-ALK; shRNA knockdown with EGFR/signaling readouts, Golgi imaging, exosome and xenograft assays for NSCLC

    PMID:29290262 PMID:39572606

    Open questions at the time
    • Molecular link between GCC2 and EGFR regulation not dissected
    • Whether EGFR effects are secondary to Golgi/trafficking disruption unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The endogenous determinant of GCC2 Golgi recruitment and the mechanism coupling its tethering, GTPase-binding, and structural roles remain unresolved.
  • Reconciliation of the Rab6/Arl1 crystal model with the negative endogenous-depletion result is unsettled
  • No unified mechanism connecting CLASP-dependent ribbon maintenance to vesicle tethering

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005794 Golgi apparatus 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-9609507 Protein localization 2
Partners
AP-1ARL1ARL4ACLASP1CLASP2HIV-1 NEFRAB6ARAB9A
Complex memberships
trans-Golgi network tethering apparatus

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GCC185 (GCC2) is a peripheral membrane protein with a C-terminal GRIP domain that targets it to the trans-Golgi network (TGN); the GRIP domain is necessary and sufficient for TGN targeting, and GCC185 localizes to a TGN subcompartment distinct from alpha2,6-sialyltransferase and cis-Golgi markers. Immunofluorescence, immunoelectron microscopy, overexpression of full-length and truncated constructs in HeLa cells The Journal of biological chemistry High 12446665
2006 GCC185 (GCC2) is a Rab9 effector required for mannose 6-phosphate receptor (MPR) recycling from late endosomes to the TGN; depletion of GCC185 triggers enhanced MPR degradation and elevated secretion of hexosaminidase, and GCC185 functions in MPR recycling both in living cells and in vitro. siRNA depletion, in vitro transport assay, functional rescue, hexosaminidase secretion assay Molecular biology of the cell High 16885419
2007 GCC185 (GCC2) is essential for endosome-to-TGN transport of shiga toxin (which accumulates in Rab11-positive recycling endosomes upon GCC185 depletion) and for maintaining Golgi ribbon organization; depletion causes Golgi fragmentation with dispersal of both cis and trans markers, while TGN38 recycling and anterograde E-cadherin transport are initially unaffected. siRNA and miRNA depletion in HeLa cells, shiga toxin trafficking assay, mannose-6-phosphate receptor distribution, immunofluorescence Traffic (Copenhagen, Denmark) High 17488291
2008 GCC185 (GCC2) is recruited to the Golgi by cooperative interaction with two small GTPases: Rab6 binds a coiled-coil domain immediately adjacent to the C-terminal GRIP domain, and Rab6 binding promotes association of Arl1 with the GRIP domain; crystal structure of Rab6 bound to the GCC185 Rab-binding domain reveals Rab6 recognizes a two-fold symmetric surface on the coiled coil. Crystal structure determination, mutagenesis of Rab-binding residues, Golgi localization assay, in vitro binding assays Cell High 18243103
2008 GCC185 (GCC2) contains at least four additional Rab GTPase binding sites distributed across its length that can bind up to 14 different Rab GTPases; a central coiled-coil domain contains a specific Rab9 binding site that is functionally important for MPR recycling to the Golgi. Yeast two-hybrid, direct biochemical binding assays, siRNA depletion with plasmid rescue, functional MPR recycling assay Molecular biology of the cell High 18946081
2009 Endogenous GCC185 (GCC2) Golgi localization does not require Rab6A/A' or Arl1; depletion of both Rab6A/A' and Arl1 had no effect on localization of endogenous GCC185 or its isolated GRIP domain, and minimal colocalization between Rab6A/A' and endogenous GCC185 was detected on Golgi membranes. Rab6A/A' and Arl1 depletion (siRNA), yeast two-hybrid (negative result for Rab6A/A' interaction with GCC185 C-terminal domain), immunofluorescence colocalization Cell Medium 19703403
2011 GCC185 (GCC2) contains two functionally distinct domains: one required for Golgi structure maintenance and a separate domain required for vesicle tethering that directly binds the clathrin adaptor AP-1; cells depleted of GCC185 accumulate MPRs in AP-1-decorated transport vesicles, indicating GCC185 tethers AP-1-coated vesicles carrying MPRs from late endosomes to the TGN. Domain deletion/rescue experiments, co-immunoprecipitation of AP-1, siRNA depletion with vesicle accumulation assay, immunofluorescence The Journal of cell biology High 21875948
2011 ARL4A directly interacts with GCC185 (GCC2) in a GTP-dependent manner via the CC2 coiled-coil sub-domain of GCC185; this interaction is required for GCC185 to recruit CLASP1 and CLASP2 to the Golgi, which is necessary for Golgi structure maintenance. Depletion of ARL4A impairs GCC185–CLASP interaction and phenocopies GCC185 depletion (Golgi fragmentation, endosome-to-Golgi transport defects). Co-immunoprecipitation, GST pulldown, siRNA depletion of ARL4A, domain deletion mapping, CLASP recruitment assay Journal of cell science High 22159419
2016 HIV-1 Nef binds to GCC185 (GCC2) via the N-terminal EEEE65 acidic domain of Nef; this interaction disrupts GCC185–Rab9 interaction, causing delocalization of CI-MPR and elevated hexosaminidase secretion, thereby disrupting retrograde vesicular transport from late endosomes to the TGN. Co-immunoprecipitation, C. elegans screen followed by biochemical characterization, hexosaminidase secretion assay, CI-MPR localization assay Biochemical and biophysical research communications Medium 27105913
2017 The GCC2-ALK fusion protein acts as a constitutively activated oncogenic kinase: it promotes IL-3-independent growth of Ba/F3 cells and leads to hyper-activation of ALK downstream signaling (MAPK, PI3K, STAT3 pathways) in HEK-293 and 293T cells; this activation is inhibited by crizotinib. Ba/F3 cell proliferation assay (IL-3 independence), ectopic expression in HEK-293/293T cells, western blot for downstream signaling, crizotinib inhibition assay Lung cancer (Amsterdam, Netherlands) Medium 29290262
2019 HIV-1 Nef assembles a multi-protein complex at the TGN through GCC185 (GCC2) as a focal scaffold; GCC185-dependent complex includes MHC-I and SFK, while Nef-dependent components include AP-1 and PI3K; siRNA knockdown of GCC185 in Jurkat T cells causes MHC-I accumulation at GCC185, linking GCC185 to Nef-mediated MHC-I downregulation. Co-immunoprecipitation in Jurkat T and THP-1 cells, siRNA knockdown of GCC185, confocal microscopy, flow cytometry for MHC-I surface levels Life sciences Medium 30953643
2024 GCC2 knockdown in NSCLC cells decreases EGFR expression and suppresses downstream growth/proliferation signaling, while also compromising Golgi structural integrity and reducing exosome secretion; these results indicate GCC2 regulates EGFR signaling and intracellular trafficking in cancer cells. shRNA-mediated GCC2 knockdown, western blot for EGFR and downstream signaling, cell proliferation/migration/EMT assays, Golgi morphology imaging, exosome secretion assay, in vivo xenograft Scientific reports Medium 39572606

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Rab and Arl GTPase family members cooperate in the localization of the golgin GCC185. Cell 140 18243103
2007 The trans-Golgi network golgin, GCC185, is required for endosome-to-Golgi transport and maintenance of Golgi structure. Traffic (Copenhagen, Denmark) 121 17488291
2002 GRIP domain-mediated targeting of two new coiled-coil proteins, GCC88 and GCC185, to subcompartments of the trans-Golgi network. The Journal of biological chemistry 110 12446665
2006 A functional role for the GCC185 golgin in mannose 6-phosphate receptor recycling. Molecular biology of the cell 103 16885419
2008 Multiple Rab GTPase binding sites in GCC185 suggest a model for vesicle tethering at the trans-Golgi. Molecular biology of the cell 84 18946081
2009 The localization of the Golgin GCC185 is independent of Rab6A/A' and Arl1. Cell 38 19703403
2011 GCC185 plays independent roles in Golgi structure maintenance and AP-1-mediated vesicle tethering. The Journal of cell biology 35 21875948
2011 ARL4A acts with GCC185 to modulate Golgi complex organization. Journal of cell science 32 22159419
2017 GCC2-ALK as a targetable fusion in lung adenocarcinoma and its enduring clinical responses to ALK inhibitors. Lung cancer (Amsterdam, Netherlands) 25 29290262
2021 GCC2 as a New Early Diagnostic Biomarker for Non-Small Cell Lung Cancer. Cancers 24 34771645
2022 Case Report: Efficacy of ensartinib treatment in pulmonary inflammatory myofibroblastic tumor with a rare GCC2-ALK fusion. Frontiers in oncology 8 36003768
2016 HIV-1 Nef binds with human GCC185 protein and regulates mannose 6 phosphate receptor recycling. Biochemical and biophysical research communications 7 27105913
2024 GCC2 promotes non-small cell lung cancer progression by maintaining Golgi apparatus integrity and stimulating EGFR signaling pathways. Scientific reports 5 39572606
2019 A novel fusion gene involving PDGFRB and GCC2 in a chronic eosinophilic leukemia patient harboring t(2;5)(q37;q31). Molecular genetics & genomic medicine 5 30697976
2019 Rare GCC2-ALK fusion G13:A20 detected by next generation sequencing in non-small cell lung cancer patients and treatment response. Translational cancer research 4 35116968
2023 Differential paired stage-specific expression of Babesia bovis cysteine-rich GCC2/GCC3 domain family proteins (BboGDP) during development within Rhipicephalus microplus. Parasites & vectors 2 36650585
2019 HIV-1 Nef-GCC185 interaction regulates assembly of cellular protein complexes at TGN targeting MHC-I downregulation. Life sciences 2 30953643
2015 Molecular and cellular characterization of GCC185: a tethering protein of the trans-Golgi network. Methods in molecular biology (Clifton, N.J.) 2 25702118

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