RICS (gene)
Encyclopedia
Rho GTPase-activating protein 32 is a protein
that in humans is encoded by the RICS gene
. 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 endosome
s. The only known domain of the RICS is the RhoGAP domain
, whilst PX-RICS has an additional Phox homology
and SH3 domain
.
activity.
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 receptor
s 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 spine
s. 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-cadherin
s, 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 FYN
controls the binding of RPTPa to RICS.
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. It has also now been shown that membrane transport of FGFR4, a N-Cadherin binding protein, is affected by PX-RICS knockdown.
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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the RICS gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. RICS has two known isoforms, RICS that are expressed primarily at neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
growth cones, and at the post synaptic membranes
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
, and PX-RICS which is more widely expressed in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
and endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...
s. The only known domain of the RICS is the RhoGAP domain
RhoGAP domain
RhoGAP domain is an evolutionary conserved protein domain ofGTPase activating proteins towards Rho/Rac/Cdc42-like small GTPases.-Human proteins containing this domain :ABR; ARHGAP1; ARHGAP10; ARHGAP11A; ARHGAP11B; ARHGAP12; ARHGAP15; ARHGAP17;...
, whilst PX-RICS has an additional Phox homology
PX domain
The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.This domain was first found in P40phox and p47phox domains of NADPH oxidase...
and SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
.
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 GTPaseRHOA
Ras homolog gene family, member A is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. In humans, it is encoded by the gene RHOA....
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
PTPRA
Receptor-type tyrosine-protein phosphatase alpha is an enzyme that in humans is encoded by the PTPRA gene.-Interactions:PTPRA has been shown to interact with Grb2 and KCNA2.-Further reading:...
. When CaMKII
Ca2+/calmodulin-dependent protein kinase
/calmodulin-dependent protein kinases II or CaM kinases II are serine/threonine-specific protein kinases that are regulated by the /calmodulin complex...
is activated by Ca2+
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
entry through NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s and inactivates RICS through phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
, which in turn increases the active GTP-bound forms of Cdc42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
and Rac1
RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
. This would thereby induce, for example, remodeling of dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
s. 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
PAK1
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.-Interactions:PAK1 has been shown to interact with C-Raf, NCK1, LIMK1, RAC1, ARHGEF2, BMX, ARPC1B, DYNLL1, Cyclin-dependent kinase 5, PAK1IP1 and CDC42....
, LIMK
LIMK1
LIM domain kinase 1 is an enzyme that in humans is encoded by the LIMK1 gene.-Interactions:LIMK1 has been shown to interact with PAK1, YWHAZ, PAK4, Cofilin 1, Neuregulin 1 and Cyclin-dependent kinase inhibitor 1C.-External links:...
, CFL1
Cofilin 1
Cofilin 1 , also known as CFL1, is a human gene, part of the ADF/cofilin family.Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner...
pathway), the most likely pathway is via Rac1. That RACS also binds to β-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
and N-cadherin
CDH2
Cadherin-2 , also known as neural cadherin is a protein that in humans is encoded by the CDH2 gene. CDH2 has also been designated as CD325 .- Function :...
s, in vivo within the PSD (which it binds to through PSD-95
DLG4
PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene....
, 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 FYN
FYN
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
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 GABARAP
GABARAP
Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the GABARAP gene.A study has screened 2000 participants representing more than 600 families of smokers and examined different genes showing linkage to nicotine addiction...
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
YWHAZ
14-3-3 protein zeta/delta is a protein that in humans is encoded by the YWHAZ gene.-Interactions:YWHAZ has been shown to interact with TSC2, LIMK1, CDC25B, AKT1, BCAR1, Interleukin-9 receptor, C-Raf, HMGN1, Vimentin, Tau protein, Protein kinase Mζ, GP1BB, GP1BA, TNFAIP3, Bcl-2-associated death...
and YWHAQ
YWHAQ
14-3-3 protein theta is a protein that in humans is encoded by the YWHAQ gene.-Interactions:YWHAQ has been shown to interact with MEF2D, Bcl-2-associated X protein, CRTC2, C-Raf, Histone deacetylase 5, NRIP1, Protein kinase Mζ, UCP3, PFKFB2, Telomerase reverse transcriptase, Bcl-2-associated death...
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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- BCAR1BCAR1Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the BCAR1 gene.-External links:* Info with links in the...
, - CDC42CDC42Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
, - CRKCRK (gene)Adapter molecule crk also known as proto-oncogene c-Crk or p38 is a protein that in humans is encoded by the CRK gene.- Function :...
, - CRKLCRKLCrk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...
, - FYNFYNProto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
, - GAB2GAB2GRB2-associated-binding protein 2 is a protein that in humans is encoded by the GAB2 gene.The protein encoded by this gene, GAB2 is an adaptor protein serving as principal activator of Phosphatidylinositol 3-kinase...
, - GRIN2BGRIN2BGlutamate [NMDA] receptor subunit epsilon-2 also known as N-methyl D-aspartate receptor subtype 2B is a protein that in humans is encoded by the GRIN2B gene.- Function :...
, - NCK1NCK1Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.-Interactions:NCK1 has been shown to interact with DNM1, EIF2B2, KHDRBS1, Lymphocyte cytosolic protein 2, EPH receptor B1, SOCS7, MINK1, MAP4K1, MAP4K4, Abl gene, WIPF1, RRAS, Wiskott-Aldrich syndrome protein,...
, - RAC1RAC1Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
, - RHOARHOARas homolog gene family, member A is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. In humans, it is encoded by the gene RHOA....
, - SHC3SHC3SHC-transforming protein 3 is a protein that in humans is encoded by the SHC3 gene.-Interactions:SHC3 has been shown to interact with RICS and TrkB.-Further reading:...
, - SrcSrc (gene)Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
, and - TrkATrkAHigh affinity nerve growth factor receptor also known as neurotrophic tyrosine kinase receptor type 1 or TRK1-transforming tyrosine kinase protein or Trk-A is a protein that in humans is encoded by the NTRK1 gene....
.
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.