RICS (gene)

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

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.

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 is_associated_with::NMDA receptors and inactivates RICS through is_associated_with::phosphorylation, which in turn increases the active GTP-bound forms of Cdc42 and Rac1. This would thereby induce, for example, remodeling of is_associated_with::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 is_associated_with::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. 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 is_associated_with::FYN controls the binding of RPTPa to RICS.

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. 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 is_associated_with::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 is_associated_with::YWHAZ and is_associated_with::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. It has also now been shown that membrane transport of FGFR4, a N-Cadherin binding protein, is affected by PX-RICS knockdown.

Interactions
RICS (gene) has been shown to interact with:


 * is_associated_with::BCAR1,
 * is_associated_with::CDC42,
 * CRK,
 * is_associated_with::CRKL,
 * is_associated_with::FYN,
 * is_associated_with::GAB2,
 * is_associated_with::GRIN2B,
 * is_associated_with::NCK1,
 * is_associated_with::RAC1,
 * is_associated_with::RHOA,
 * is_associated_with::SHC3,
 * Src, and
 * is_associated_with::TrkA.

The is_associated_with::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.