| Structural highlights
Disease
[BIG2_HUMAN] Defects in ARFGEF2 are the cause of autosomal recessive periventricular nodular heterotopia type 2 (PVNH2) [MIM:608097]; also known as periventricular heterotopia with microcephaly autosomal recessive. PVNH is a developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. PVNH2 is an autosomal recessive form characterized by microcephaly (small brain), severe developmental delay and recurrent infections. No anomalies extrinsic to the central nervous system, such as dysmorphic features or grossly abnormal endocrine or other conditions, are associated with PVNH2.[1]
Function
[BIG2_HUMAN] Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extend on ARF5 and ARF6. Promotes the activation of ARF1/ARF5/ARF6 through replacement of GDP with GTP. Involved in the regulation of Golgi vesicular transport. Required for the integrity of the endosomal compartment. Involved in trafficking from the trans-Golgi network (TGN) to endosomes and is required for membrane association of the AP-1 complex and GGA1. Seems to be involved in recycling of the transferrin receptor from recycling endosomes to the plasma membrane. Probably is involved in the exit of GABA(A) receptors from the endoplasmic reticulum. Involved in constitutive release of tumor necrosis factor receptor 1 via exosome-like vesicles; the function seems to involve PKA and specifically PRKAR2B. Proposed to act as A kinase-anchoring protein (AKAP) and may mediate crosstalk between Arf and PKA pathways.[2] [3] [4] [5] [6] [7] [8]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, Grant PE, Shugart YY, Imitola J, Khoury SJ, Guerrini R, Walsh CA. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004 Jan;36(1):69-76. Epub 2003 Nov 30. PMID:14647276 doi:10.1038/ng1276
- ↑ Shinotsuka C, Waguri S, Wakasugi M, Uchiyama Y, Nakayama K. Dominant-negative mutant of BIG2, an ARF-guanine nucleotide exchange factor, specifically affects membrane trafficking from the trans-Golgi network through inhibiting membrane association of AP-1 and GGA coat proteins. Biochem Biophys Res Commun. 2002 Jun 7;294(2):254-60. PMID:12051703 doi:10.1016/S0006-291X(02)00456-4
- ↑ Li H, Adamik R, Pacheco-Rodriguez G, Moss J, Vaughan M. Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2). Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1627-32. Epub 2003 Feb 5. PMID:12571360 doi:10.1073/pnas.0337678100
- ↑ Shin HW, Morinaga N, Noda M, Nakayama K. BIG2, a guanine nucleotide exchange factor for ADP-ribosylation factors: its localization to recycling endosomes and implication in the endosome integrity. Mol Biol Cell. 2004 Dec;15(12):5283-94. Epub 2004 Sep 22. PMID:15385626 doi:10.1091/mbc.E04-05-0388
- ↑ Shen X, Xu KF, Fan Q, Pacheco-Rodriguez G, Moss J, Vaughan M. Association of brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2) with recycling endosomes during transferrin uptake. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2635-40. Epub 2006 Feb 13. PMID:16477018 doi:10.1073/pnas.0510599103
- ↑ Islam A, Shen X, Hiroi T, Moss J, Vaughan M, Levine SJ. The brefeldin A-inhibited guanine nucleotide-exchange protein, BIG2, regulates the constitutive release of TNFR1 exosome-like vesicles. J Biol Chem. 2007 Mar 30;282(13):9591-9. Epub 2007 Feb 2. PMID:17276987 doi:10.1074/jbc.M607122200
- ↑ Islam A, Jones H, Hiroi T, Lam J, Zhang J, Moss J, Vaughan M, Levine SJ. cAMP-dependent protein kinase A (PKA) signaling induces TNFR1 exosome-like vesicle release via anchoring of PKA regulatory subunit RIIbeta to BIG2. J Biol Chem. 2008 Sep 12;283(37):25364-71. doi: 10.1074/jbc.M804966200. Epub 2008, Jul 14. PMID:18625701 doi:10.1074/jbc.M804966200
- ↑ Boal F, Stephens DJ. Specific functions of BIG1 and BIG2 in endomembrane organization. PLoS One. 2010 Mar 25;5(3):e9898. doi: 10.1371/journal.pone.0009898. PMID:20360857 doi:10.1371/journal.pone.0009898
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