Chimerin

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Chimerin is a type of nerve tissue protein. [1]

Chimerins are a family of non-protein kinase C phorbol ester receptors. They were the first phorbol ester receptors to be discovered within this family. They are represented as a family of four closely bound GAPs1 (GTPase-activating proteins). These small GTPases were once characterized as high affinity intracellular receptors for the second messenger diacylglycerol (DAG) and the phorbol ester tumor promoters. The name stems from their resemblance to the "chimera."

Contents

Types

Types include:

There are four known isoforms of the chimerin protein. These include α1, α2, β1, and β2. α1-Chimerin was the first protein to be isolated from the brain. The other domains were discovered through alternative splicing. The α and β isoforms are almost identical, the key difference stems from the SH2 domain at the N-terminal.

α1

α1-Chimerin is a GTPase-activating protein in the brain that effects the ras related p21rac. α1-Chimerin is also able to regulate dendritic spinal density by binding to NMDA receptors at the NR2A subunit. Over expression of this protein in hippocampus tissue can inhibit the formation of new spines and remove existing spines. [2] [3] Mutations found in α-chi-merin lead to the Duane retraction syndrome 2. Beta-chimerin (Rho GTPase-activating protein 3, 468aa) is mainly found in the brain and pancreas and the expression is in the form of reduced malignant gliomas. [4] Changes in cytoskeletal organization are due to the action on Rac.

α2

α2-Chimerin acts in a similar manner to α1-chimerin, but is primarily found in the brain and testes. It is also an SH2 containing GTPase activating protein and bears many similarities in function. It Is derived from alternative splicing of the α-chimera gene. [5]

α2-Chimerin was shown to be involved and important in cognitive development. The expression of α2-chimerin is present in development so α2-chimerin is essential for cognitive function as it directly leads to functioning cognitive ability in adulthood. [6] α2-Chimerin also plays a role in the ocular motor system. Mutations in α2-chimerin can cause disorders such as Duane Retraction Syndrome as it changes the signals on how the eye moves. [7]

β2

β2-Chimerin has been shown to play a role in breast cancer. In breast cancer cells the amount of β2-chimerin messengers are extremely low. When introduced to the cancerous cells β2-chimerin then causes the G1 cell cycle  to stop and therefore it stops the cells from multiplying. [8]

β2-Chimerin can be linked to a fusion gene that is associated with a key insulin receptor that causes people to have decreased levels of insulin. [9]

Related Research Articles

GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a protein domain common to many GTPases.

<span class="mw-page-title-main">G protein</span> Type of proteins

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.

<span class="mw-page-title-main">Insulin receptor</span> Mammalian protein found in Homo sapiens

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis, a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Insulin-like growth factor 1 receptor</span> Cell surface tyrosine kinase associated receptor, quiche mediates the effects of Igf-1

The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 (IGF-1) and by a related hormone called IGF-2. It belongs to the large class of tyrosine kinase receptors. This receptor mediates the effects of IGF-1, which is a polypeptide protein hormone similar in molecular structure to insulin. IGF-1 plays an important role in growth and continues to have anabolic effects in adults – meaning that it can induce hypertrophy of skeletal muscle and other target tissues. Mice lacking the IGF-1 receptor die late in development, and show a dramatic reduction in body mass. This testifies to the strong growth-promoting effect of this receptor.

<span class="mw-page-title-main">Chimerin 1</span> Protein-coding gene in the species Homo sapiens

Chimerin 1 (CHN1), also known as alpha-1-chimerin, n-chimerin, is a protein which in humans is encoded by the CHN1 gene.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog is a protein that in humans is encoded by the Cdc42 gene. Cdc42 is 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.

<span class="mw-page-title-main">RAC1</span> Protein-coding gene in the species Homo sapiens

Rac1, also known as Ras-related C3 botulinum toxin substrate 1, is a protein found in human cells. It is encoded by the RAC1 gene. This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions.

<span class="mw-page-title-main">Transforming protein RhoA</span> Protein and coding gene in humans

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.

<span class="mw-page-title-main">RAS p21 protein activator 1</span> Protein-coding gene in the species Homo sapiens

RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:

<span class="mw-page-title-main">RACGAP1</span> Protein-coding gene in the species Homo sapiens

Rac GTPase-activating protein 1 is an enzyme that in humans is encoded by the RACGAP1 gene.

<span class="mw-page-title-main">ARHGEF7</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ARHGEF7 gene.

<span class="mw-page-title-main">ARHGEF6</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 6 is a protein that, in humans, is encoded by the ARHGEF6 gene.

<span class="mw-page-title-main">DLC1</span> Protein-coding gene in the species Homo sapiens

Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.

<span class="mw-page-title-main">Chimerin 2</span> Protein-coding gene in the species Homo sapiens

Chimerin 2 (beta-chimaerin) is a protein that in humans is encoded by the CHN2 gene.

<span class="mw-page-title-main">SYNGAP1</span> Protein in Homo sapiens

Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene. SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability, epilepsy, autism and sensory processing deficits.

<span class="mw-page-title-main">RICS (gene)</span> Protein-coding gene in the species Homo sapiens

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 endosomes. The only known domain of the RICS is the RhoGAP domain, whilst PX-RICS has an additional Phox homology and SH3 domain.

<span class="mw-page-title-main">Dishevelled</span> Family of proteins

Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the SPATS1 protein when regulating the Wnt Signalling pathway.

<span class="mw-page-title-main">Pregnenolone sulfate</span> Chemical compound

Pregnenolone sulfate is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects.

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.

References

  1. ↑ Chimerin+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
  2. ↑ Van de Ven TJ, VanDongen HM, VanDongen AM (October 2005). "The nonkinase phorbol ester receptor alpha 1-chimerin binds the NMDA receptor NR2A subunit and regulates dendritic spine density". The Journal of Neuroscience. 25 (41): 9488–9496. doi:10.1523/JNEUROSCI.2450-05.2005. PMC   6725706 . PMID   16221859.
  3. ↑ Lackie JM (2013). The Dictionary of Cell and Molecular Biology. Academic Press. p. 119.
  4. ↑ Cammack R, Atwood T, Campbell P, Parish H, Smith A, Vella F, Stirling J (2006). Oxford Dictionary of Biochemistry and Molecular Biology. Oxford University Press. ISBN   9780198529170.
  5. ↑ Hall C, Sin WC, Teo M, Michael GJ, Smith P, Dong JM, et al. (August 1993). "Alpha 2-chimerin, an SH2-containing GTPase-activating protein for the ras-related protein p21rac derived by alternate splicing of the human n-chimerin gene, is selectively expressed in brain regions and testes". Molecular and Cellular Biology. 13 (8): 4986–4998. doi:10.1128/MCB.13.8.4986. PMC   360144 . PMID   8336731.
  6. ↑ Iwata R, Ohi K, Kobayashi Y, Masuda A, Iwama M, Yasuda Y, et al. (September 2014). "RacGAP α2-chimaerin function in development adjusts cognitive ability in adulthood". Cell Reports. 8 (5): 1257–1264. doi: 10.1016/j.celrep.2014.07.047 . PMID   25159148.
  7. ↑ Carretero-Rodriguez L, Guðjónsdóttir R, Poparic I, Reilly ML, Chol M, Bianco IH, et al. (August 2021). "The Rac-GAP alpha2-Chimaerin Signals via CRMP2 and Stathmins in the Development of the Ocular Motor System". The Journal of Neuroscience. 41 (31): 6652–6672. doi:10.1523/JNEUROSCI.0983-19.2021. PMC   8336708 . PMID   34168008.
  8. ↑ Yang C, Liu Y, Leskow FC, Weaver VM, Kazanietz MG (July 2005). "Rac-GAP-dependent inhibition of breast cancer cell proliferation by {beta}2-chimerin". The Journal of Biological Chemistry. 280 (26): 24363–24370. doi: 10.1074/jbc.M411629200 . PMID   15863513. S2CID   84567020.
  9. ↑ Suliman SG, Stanik J, McCulloch LJ, Wilson N, Edghill EL, Misovicova N, et al. (December 2009). "Severe insulin resistance and intrauterine growth deficiency associated with haploinsufficiency for INSR and CHN2: new insights into synergistic pathways involved in growth and metabolism". Diabetes. 58 (12): 2954–2961. doi:10.2337/db09-0787. PMC   2780873 . PMID   19720790.
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