RICS (gene) explained

Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene.^[1] RICS has two known isoforms, RICS that are expressed primarily at neurite growth cones, and at the post synaptic membranes, and PX-RICS which is more widely expressed in the endoplasmic reticulum, Golgi apparatus and endosomes.^[2] The only known domain of the RICS is the RhoGAP domain, whilst PX-RICS has an additional Phox homology and SH3 domain.

Function

RICS (a.k.a. GRIT/Arhgap32) is a neuron-associated GTPase-activating protein that may regulate dendritic spine morphology and strength by modulating Rho GTPase activity.^{[1] [2]}

Isoforms

RICS

Experiments have shown that knocking down RICS, or just knocking out its GAP or C-terminal TrkA binding site, results in abnormally extended neurites, and blocks NGF regulated outgrowth.^[3]

The GAP activity of RICS is known to be regulated by two phosphorylation sites, one controlled by CaMKII, and the other by RPTPa. When CaMKII is activated by Ca²⁺ entry through NMDA receptors and inactivates RICS through phosphorylation, which in turn increases the active GTP-bound forms of Cdc42 and Rac1. This would thereby induce, for example, remodeling of dendritic spines. Because it has been shown in some experiments that Cdc42 does not affect spine morphology, whilst others have shown that Rac1 does (via the PAK1, LIMK, CFL1 pathway), the most likely pathway is via Rac1. That RACS also binds to β-catenin and N-cadherins, in vivo within the PSD (which it binds to through PSD-95, and weak binding to the NR2 subunits) suggests that there may be another pathway for it modifying spine structure as well.^[2] The RPTPa controlled phosphorylation site controls the specificity of the GAP activity, through a mechanism thought to involve movement of the c-terminal region of RICS. In the phosphorylated state, RICS can affect Rac, Rho and Cdc42, but after dephosphorylation by RPTPa it can only affect Rac. A further phosphorylation site, regulated by FYN controls the binding of RPTPa to RICS.^[4]

PX-RICS

PX-RICS is the dominant isoform expressed during nervous system development. It is known to have much lower GAP activity than RICS. Although it is more generally expressed than RICS, it is still known to inhibit neuronal elongation.^[5] Furthering the idea that it is a synaptically relevant isoform is that it is known to bind NR2B and PSD95 in vivo.

PX-RICS is known to be involved in transport of certain synaptic proteins which lack ER export signals, from the endoplasmic reticulum, to the Golgi apparatus. This has been shown for the β-catenin and N-cadherin, the later of which lacks the ER export signal, and the former which binds the later within the ER as a necessary but not sufficient part of its export process. PX-RICS was found to be a necessary component for the export of this complex to the Golgi and then onwards to the cellular membrane. PX-RICS is thought to do this by first localizing to the ER membrane---this it does by binding to GABARAP which binds ER, and through its Phox homology domain, which has a high binding affinity for Pi4P, the predominant phosphoinositide in the endoplasmic reticulum and Golgi apparatus. PX-RICS is then thought to bind a heterodimer of the 14-3-3 proteins encoded by YWHAZ and YWHAQ genes. The site were this binding occurs is a RSKSDP site in PX-RICS c-terminal, which is phosphorylated by CAMKII to encourage the binding.^[6] It has also now been shown that membrane transport of FGFR4, a N-Cadherin binding protein, is affected by PX-RICS knockdown.^[7]

Interactions

RICS (gene) has been shown to interact with:

• BCAR1,^[8]
• CDC42,^{[3] [8]}
• CRK,^[8]
• CRKL,^[3]
• FYN,^[9]
• GAB2,^[8]
• GRIN2B,
• NCK1,^[8]
• RAC1,^[8]
• RHOA,^{[3] [10]}
• SHC3,^[3]
• Src,^[11] and
• TrkA.^[3]

The Mir-132 microRNA has been described as targeting the mRNA from this gene for degradation; this is thought to be important in the regulation of neuronal development.^[12]

Further reading

• Hayashi T, Okabe T, Nasu-Nishimura Y, Sakaue F, Ohwada S, Matsuura K, Akiyama T, Nakamura T . PX-RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development. . Genes Cells . 12 . 8 . 929–39 . 2007 . 17663722 . 10.1111/j.1365-2443.2007.01101.x . 22118853 . free .
• Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY . A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. . Cell . 125 . 4 . 801–14 . 2006 . 16713569 . 10.1016/j.cell.2006.03.032 . 13709685 . free .
• Benzinger A, Muster N, Koch HB, Yates JR, Hermeking H . Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer. . Mol. Cell. Proteomics . 4 . 6 . 785–95 . 2005 . 15778465 . 10.1074/mcp.M500021-MCP200 . free .
• Nakazawa T, Watabe AM, Tezuka T, Yoshida Y, Yokoyama K, Umemori H, Inoue A, Okabe S, Manabe T, Yamamoto T . p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-d-aspartate receptor signaling. . Mol. Biol. Cell . 14 . 7 . 2921–34 . 2004 . 12857875 . 165687 . 10.1091/mbc.E02-09-0623 .
• Zhao C, Ma H, Bossy-Wetzel E, Lipton SA, Zhang Z, Feng GS . GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2. . J. Biol. Chem. . 278 . 36 . 34641–53 . 2003 . 12819203 . 10.1074/jbc.M304594200 . free .
• Taniguchi S, Liu H, Nakazawa T, Yokoyama K, Tezuka T, Yamamoto T . p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn. . Biochem. Biophys. Res. Commun. . 306 . 1 . 151–5 . 2003 . 12788081 . 10.1016/S0006-291X(03)00923-9 .
• Okabe T, Nakamura T, Nishimura YN, Kohu K, Ohwada S, Morishita Y, Akiyama T . RICS, a novel GTPase-activating protein for Cdc42 and Rac1, is involved in the beta-catenin-N-cadherin and N-methyl-D-aspartate receptor signaling. . J. Biol. Chem. . 278 . 11 . 9920–7 . 2003 . 12531901 . 10.1074/jbc.M208872200 . free .
• Gardiner EM, Pestonjamasp KN, Bohl BP, Chamberlain C, Hahn KM, Bokoch GM . Spatial and temporal analysis of Rac activation during live neutrophil chemotaxis. . Curr. Biol. . 12 . 23 . 2029–34 . 2003 . 12477392 . 10.1016/S0960-9822(02)01334-9 . 13589833 . free .
• Moon SY, Zang H, Zheng Y . Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP. . J. Biol. Chem. . 278 . 6 . 4151–9 . 2003 . 12454018 . 10.1074/jbc.M207789200 . free .
• Nakamura T, Komiya M, Sone K, Hirose E, Gotoh N, Morii H, Ohta Y, Mori N . Grit, a GTPase-activating protein for the Rho family, regulates neurite extension through association with the TrkA receptor and N-Shc and CrkL/Crk adapter molecules. . Mol. Cell. Biol. . 22 . 24 . 8721–34 . 2003 . 12446789 . 139861 . 10.1128/MCB.22.24.8721-8734.2002 .
• Nakayama M, Kikuno R, Ohara O . Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs. . Genome Res. . 12 . 11 . 1773–84 . 2003 . 12421765 . 187542 . 10.1101/gr.406902 .
• Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O . Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. . DNA Res. . 5 . 5 . 277–86 . 1999 . 9872452 . 10.1093/dnares/5.5.277 . free .

Notes and References

1. Web site: Entrez Gene: RICS Rho GTPase-activating protein.
2. Okabe T, Nakamura T, Nishimura YN, Kohu K, Ohwada S, Morishita Y, Akiyama T . RICS, a novel GTPase-activating protein for Cdc42 and Rac1, is involved in the beta-catenin-N-cadherin and N-methyl-D-aspartate receptor signaling . J. Biol. Chem. . 278 . 11 . 9920–7 . March 2003 . 12531901 . 10.1074/jbc.M208872200 . free .
3. Nakamura T, Komiya M, Sone K, Hirose E, Gotoh N, Morii H, Ohta Y, Mori N . Grit, a GTPase-activating protein for the Rho family, regulates neurite extension through association with the TrkA receptor and N-Shc and CrkL/Crk adapter molecules . Mol. Cell. Biol. . 22 . 24 . 8721–34 . December 2002 . 12446789 . 139861 . 10.1128/MCB.22.24.8721-8734.2002 .
4. Chagnon MJ, Wu CL, Nakazawa T, Yamamoto T, Noda M, Blanchetot C, Tremblay ML . Receptor tyrosine phosphatase sigma (RPTPσ) regulates, p250GAP, a novel substrate that attenuates Rac signaling . Cell. Signal. . 22 . 11 . 1626–33 . November 2010 . 20550964 . 10.1016/j.cellsig.2010.06.001 .
5. Hayashi T, Okabe T, Nasu-Nishimura Y, Sakaue F, Ohwada S, Matsuura K, Akiyama T, Nakamura T . PX-RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development . Genes Cells . 12 . 8 . 929–39 . August 2007 . 17663722 . 10.1111/j.1365-2443.2007.01101.x . 22118853 . free .
6. Nakamura T, Hayashi T, Mimori-Kiyosue Y, Sakaue F, Matsuura K, Iemura S, Natsume T, Akiyama T . The PX-RICS-14-3-3zeta/theta complex couples N-cadherin-beta-catenin with dynein-dynactin to mediate its export from the endoplasmic reticulum . J. Biol. Chem. . 285 . 21 . 16145–54 . May 2010 . 20308060 . 2871483 . 10.1074/jbc.M109.081315 . free .
7. Nakamura T, Hayashi T, Nasu-Nishimura Y, Sakaue F, Morishita Y, Okabe T, Ohwada S, Matsuura K, Akiyama T . PX-RICS mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex . Genes Dev. . 22 . 9 . 1244–56 . May 2008 . 18451111 . 2335319 . 10.1101/gad.1632308 .
8. Zhao C, Ma H, Bossy-Wetzel E, Lipton SA, Zhang Z, Feng GS . GC-GAP, a Rho family GTPase-activating protein that interacts with signaling adapters Gab1 and Gab2 . J. Biol. Chem. . 278 . 36 . 34641–53 . Sep 2003 . 12819203 . 10.1074/jbc.M304594200 . free .
9. Taniguchi S, Liu H, Nakazawa T, Yokoyama K, Tezuka T, Yamamoto T . p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn . Biochem. Biophys. Res. Commun. . 306 . 1 . 151–5 . Jun 2003 . 12788081 . 10.1016/S0006-291X(03)00923-9 .
10. Nakazawa T, Watabe AM, Tezuka T, Yoshida Y, Yokoyama K, Umemori H, Inoue A, Okabe S, Manabe T, Yamamoto T . p250GAP, a novel brain-enriched GTPase-activating protein for Rho family GTPases, is involved in the N-methyl-d-aspartate receptor signaling . Mol. Biol. Cell . 14 . 7 . 2921–34 . Jul 2003 . 12857875 . 165687 . 10.1091/mbc.E02-09-0623 .
11. Moon SY, Zang H, Zheng Y . Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP . J. Biol. Chem. . 278 . 6 . 4151–9 . Feb 2003 . 12454018 . 10.1074/jbc.M207789200 . free .
12. Vo N, Klein ME, Varlamova O, Keller DM, Yamamoto T, Goodman RH, Impey S . A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis . Proc. Natl. Acad. Sci. U.S.A. . 102 . 45 . 16426–31 . November 2005 . 16260724 . 1283476 . 10.1073/pnas.0508448102 . free .