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Identification
HMDB Protein ID HMDBP14446
Secondary Accession Numbers None
Name Girdin
Synonyms
  1. Akt phosphorylation enhancer
  2. Coiled-coil domain-containing protein 88A
  3. G alpha-interacting vesicle-associated protein
  4. Girders of actin filament
  5. Hook-related protein 1
  6. APE
  7. GIV
  8. HkRP1
Gene Name CCDC88A
Protein Type Unknown
Biological Properties
General Function Not Available
Specific Function Bifunctional modulator of guanine nucleotide-binding proteins (G proteins) (PubMed:19211784, PubMed:27621449). Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates guanine nucleotide-binding protein G(i) alpha subunits (PubMed:19211784, PubMed:21954290, PubMed:23509302, PubMed:25187647). Also acts as a guanine nucleotide dissociation inhibitor for guanine nucleotide-binding protein G(s) subunit alpha GNAS (PubMed:27621449). Essential for cell migration (PubMed:20462955, PubMed:16139227, PubMed:19211784, PubMed:21954290). Interacts in complex with G(i) alpha subunits with the EGFR receptor, retaining EGFR at the cell membrane following ligand stimulation and promoting EGFR signaling which triggers cell migration (PubMed:20462955). Binding to Gi-alpha subunits displaces the beta and gamma subunits from the heterotrimeric G-protein complex which enhances phosphoinositide 3-kinase (PI3K)-dependent phosphorylation and kinase activity of AKT1/PKB (PubMed:19211784). Phosphorylation of AKT1/PKB induces the phosphorylation of downstream effectors GSK3 and FOXO1/FKHR, and regulates DNA replication and cell proliferation (By similarity). Binds in its tyrosine-phosphorylated form to the phosphatidylinositol 3-kinase (PI3K) regulatory subunit PIK3R1 which enables recruitment of PIK3R1 to the EGFR receptor, enhancing PI3K activity and cell migration (PubMed:21954290). Plays a role as a key modulator of the AKT-mTOR signaling pathway, controlling the tempo of the process of newborn neuron integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Inhibition of G(s) subunit alpha GNAS leads to reduced cellular levels of cAMP and suppression of cell proliferation (PubMed:27621449). Essential for the integrity of the actin cytoskeleton (PubMed:16139227, PubMed:19211784). Required for formation of actin stress fibers and lamellipodia (PubMed:15882442). May be involved in membrane sorting in the early endosome (PubMed:15882442). Plays a role in ciliogenesis and cilium morphology and positioning and this may partly be through regulation of the localization of scaffolding protein CROCC/Rootletin (PubMed:27623382).
Pathways Not Available
Reactions Not Available
GO Classification
Biological Process
regulation of neuron projection development
cytoskeleton-dependent intracellular transport
regulation of cell proliferation
regulation of DNA replication
cytoplasmic microtubule organization
membrane organization
cell migration
DNA replication
regulation of actin cytoskeleton organization
nervous system development
activation of protein kinase B activity
maintenance of protein location in plasma membrane
positive regulation of cilium assembly
positive regulation of protein localization to cilium
lamellipodium assembly
TOR signaling
regulation of protein phosphorylation
activation of protein kinase activity
small GTPase mediated signal transduction
positive regulation of epidermal growth factor receptor signaling pathway
positive regulation of stress fiber assembly
Cellular Component
cytosol
centrosome
cytoplasm
centriole
endoplasmic reticulum
plasma membrane
Golgi apparatus
COPI-coated Golgi to ER transport vesicle
lamellipodium
ciliary basal body
membrane
cytoplasmic vesicle
Molecular Function
actin binding
G-protein alpha-subunit binding
SH2 domain binding
insulin receptor binding
epidermal growth factor receptor binding
phosphatidylinositol binding
dynein light intermediate chain binding
G-protein gamma-subunit binding
GDP-dissociation inhibitor activity
protein homodimerization activity
microtubule binding
protein kinase C binding
guanyl-nucleotide exchange factor activity
vascular endothelial growth factor receptor 2 binding
protein kinase B binding
Cellular Location Not Available
Gene Properties
Chromosome Location Not Available
Locus Not Available
SNPs Not Available
Gene Sequence Not Available
Protein Properties
Number of Residues 1871
Molecular Weight 216039.89
Theoretical pI 6.219
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence Not Available
GenBank ID Protein Not Available
UniProtKB/Swiss-Prot ID Q3V6T2
UniProtKB/Swiss-Prot Entry Name GRDN_HUMAN
PDB IDs
GenBank Gene ID Not Available
GeneCard ID Not Available
GenAtlas ID Not Available
HGNC ID Not Available
References
General References
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  5. Bechtel S, Rosenfelder H, Duda A, Schmidt CP, Ernst U, Wellenreuther R, Mehrle A, Schuster C, Bahr A, Blocker H, Heubner D, Hoerlein A, Michel G, Wedler H, Kohrer K, Ottenwalder B, Poustka A, Wiemann S, Schupp I: The full-ORF clone resource of the German cDNA Consortium. BMC Genomics. 2007 Oct 31;8:399. [PubMed:17974005 ]
  6. Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M: Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. 2005 Sep;9(3):389-402. [PubMed:16139227 ]
  7. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA, Brunak S, Mann M: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal. 2010 Jan 12;3(104):ra3. doi: 10.1126/scisignal.2000475. [PubMed:20068231 ]
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  12. Simpson F, Martin S, Evans TM, Kerr M, James DE, Parton RG, Teasdale RD, Wicking C: A novel hook-related protein family and the characterization of hook-related protein 1. Traffic. 2005 Jun;6(6):442-58. doi: 10.1111/j.1600-0854.2005.00289.x. [PubMed:15882442 ]
  13. Le-Niculescu H, Niesman I, Fischer T, DeVries L, Farquhar MG: Identification and characterization of GIV, a novel Galpha i/s-interacting protein found on COPI, endoplasmic reticulum-Golgi transport vesicles. J Biol Chem. 2005 Jun 10;280(23):22012-20. doi: 10.1074/jbc.M501833200. Epub 2005 Mar 4. [PubMed:15749703 ]
  14. Enomoto A, Ping J, Takahashi M: Girdin, a novel actin-binding protein, and its family of proteins possess versatile functions in the Akt and Wnt signaling pathways. Ann N Y Acad Sci. 2006 Nov;1086:169-84. doi: 10.1196/annals.1377.016. [PubMed:17185515 ]
  15. Garcia-Marcos M, Ghosh P, Farquhar MG: GIV is a nonreceptor GEF for G alpha i with a unique motif that regulates Akt signaling. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3178-83. doi: 10.1073/pnas.0900294106. Epub 2009 Feb 11. [PubMed:19211784 ]
  16. Ghosh P, Beas AO, Bornheimer SJ, Garcia-Marcos M, Forry EP, Johannson C, Ear J, Jung BH, Cabrera B, Carethers JM, Farquhar MG: A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate. Mol Biol Cell. 2010 Jul 1;21(13):2338-54. doi: 10.1091/mbc.e10-01-0028. Epub 2010 May 12. [PubMed:20462955 ]
  17. Lin C, Ear J, Pavlova Y, Mittal Y, Kufareva I, Ghassemian M, Abagyan R, Garcia-Marcos M, Ghosh P: Tyrosine phosphorylation of the Galpha-interacting protein GIV promotes activation of phosphoinositide 3-kinase during cell migration. Sci Signal. 2011 Sep 27;4(192):ra64. doi: 10.1126/scisignal.2002049. [PubMed:21954290 ]
  18. Lopez-Sanchez I, Garcia-Marcos M, Mittal Y, Aznar N, Farquhar MG, Ghosh P: Protein kinase C-theta (PKCtheta) phosphorylates and inhibits the guanine exchange factor, GIV/Girdin. Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5510-5. doi: 10.1073/pnas.1303392110. Epub 2013 Mar 18. [PubMed:23509302 ]
  19. Lin C, Ear J, Midde K, Lopez-Sanchez I, Aznar N, Garcia-Marcos M, Kufareva I, Abagyan R, Ghosh P: Structural basis for activation of trimeric Gi proteins by multiple growth factor receptors via GIV/Girdin. Mol Biol Cell. 2014 Nov 5;25(22):3654-71. doi: 10.1091/mbc.E14-05-0978. Epub 2014 Sep 3. [PubMed:25187647 ]
  20. Parag-Sharma K, Leyme A, DiGiacomo V, Marivin A, Broselid S, Garcia-Marcos M: Membrane Recruitment of the Non-receptor Protein GIV/Girdin (Galpha-interacting, Vesicle-associated Protein/Girdin) Is Sufficient for Activating Heterotrimeric G Protein Signaling. J Biol Chem. 2016 Dec 30;291(53):27098-27111. doi: 10.1074/jbc.M116.764431. Epub 2016 Nov 18. [PubMed:27864364 ]
  21. Gupta V, Bhandari D, Leyme A, Aznar N, Midde KK, Lo IC, Ear J, Niesman I, Lopez-Sanchez I, Blanco-Canosa JB, von Zastrow M, Garcia-Marcos M, Farquhar MG, Ghosh P: GIV/Girdin activates Galphai and inhibits Galphas via the same motif. Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):E5721-30. doi: 10.1073/pnas.1609502113. Epub 2016 Sep 12. [PubMed:27621449 ]
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  25. Authors unspecified: Correction for Kalogriopoulos et al., Structural basis for GPCR-independent activation of heterotrimeric Gi proteins. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20794. doi: 10.1073/pnas.1916094116. Epub 2019 Sep 30. [PubMed:31570568 ]