RICS (a.k.a. GRIT/Arhgap32) is a neuron-associated GTPase-activating protein that may regulate dendritic spine morphology and strength by modulatingRho GTPase activity.[5][6]
Experiments have shown that knocking down RICS, or just knocking out its GAP orC-terminalTrkA binding site, results in abnormally extended neurites, and blocksNGF regulated outgrowth.[7]
The GAP activity of RICS is known to be regulated by two phosphorylation sites, one controlled by CaMKII, and the other byRPTPa. WhenCaMKII is activated byCa2+ entry throughNMDA receptors and inactivates RICS throughphosphorylation, which in turn increases the active GTP-bound forms ofCdc42 andRac1. This would thereby induce, for example, remodeling ofdendritic spines. Because it has been shown in some experiments that Cdc42 does not affect spine morphology, whilst others have shown that Rac1 does (via thePAK1,LIMK,CFL1 pathway), the most likely pathway is via Rac1. That RACS also binds toβ-catenin andN-cadherins, in vivo within the PSD (which it binds to throughPSD-95, and weak binding to the NR2 subunits) suggests that there may be another pathway for it modifying spine structure as well.[6] 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 byFYN controls the binding of RPTPa to RICS.[8]
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.[9] 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 toGABARAP 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 byYWHAZ andYWHAQ 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.[10] It has also now been shown that membrane transport of FGFR4, a N-Cadherin binding protein, is affected by PX-RICS knockdown.[11]
TheMir-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.[16]
^Taniguchi S, Liu H, Nakazawa T, Yokoyama K, Tezuka T, Yamamoto T (Jun 2003). "p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn".Biochem. Biophys. Res. Commun.306 (1):151–5.doi:10.1016/S0006-291X(03)00923-9.PMID12788081.
Taniguchi S, Liu H, Nakazawa T, Yokoyama K, Tezuka T, Yamamoto T (2003). "p250GAP, a neural RhoGAP protein, is associated with and phosphorylated by Fyn".Biochem. Biophys. Res. Commun.306 (1):151–5.doi:10.1016/S0006-291X(03)00923-9.PMID12788081.
