Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene. [5] 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. [6] The only known domain of the RICS is the RhoGAP domain, whilst PX-RICS has an additional Phox homology and SH3 domain.
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. [5] [6]
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. [7]
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. [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 by FYN 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 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. [10] It has also now been shown that membrane transport of FGFR4, a N-Cadherin binding protein, is affected by PX-RICS knockdown. [11]
RICS (gene) has been shown to interact with:
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. [16]
Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.
Adapter molecule crk also known as proto-oncogene c-Crk is a protein that in humans is encoded by the CRK gene.
Cell division control protein 42 homolog, also known as Cdc42, is a protein involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.
Beta-catenin-interacting protein 1 is a protein that is encoded in humans by the CTNNBIP1 gene.
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.
Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.
Rho GTPase-activating protein 1 is an enzyme that in humans is encoded by the ARHGAP1 gene.
Ras GTPase-activating-like protein IQGAP1 (IQGAP1) also known as p195 is a ubiquitously expressed protein that in humans is encoded by the IQGAP1 gene. IQGAP1 is a scaffold protein involved in regulating various cellular processes ranging from organization of the actin cytoskeleton, transcription, and cellular adhesion to regulating the cell cycle.
Rac2 is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RAC2.
Dock180, also known as DOCK1, is a large protein involved in intracellular signalling networks. It is the mammalian ortholog of the C. elegans protein CED-5 and belongs to the DOCK family of Guanine nucleotide exchange factors (GEFs).
Rho GDP-dissociation inhibitor 1 is a protein that in humans is encoded by the ARHGDIA gene.
Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.
Beta-chimaerin is a protein that in humans is encoded by the CHN2 gene.
RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.
SHC-transforming protein 3 is a protein that in humans is encoded by the SHC3 gene.
Rnd2 is a small signaling G protein, and is a member of the Rnd subgroup of the Rho family of GTPases. It is encoded by the gene RND2.
Guanine nucleotide-binding protein subunit alpha-13 is a protein that in humans is encoded by the GNA13 gene.
Long-term potentiation (LTP), thought to be the cellular basis for learning and memory, involves a specific signal transmission process that underlies synaptic plasticity. Among the many mechanisms responsible for the maintenance of synaptic plasticity is the cadherin–catenin complex. By forming complexes with intracellular catenin proteins, neural cadherins (N-cadherins) serve as a link between synaptic activity and synaptic plasticity, and play important roles in the processes of learning and memory.
