Cell division control protein 42 homolog (Cdc42 or CDC42) 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, [5] [6] and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.
Human Cdc42 is a small GTPase of the Rho family, which regulates signaling pathways that control diverse cellular functions including cell morphology, cell migration, endocytosis, cell polarity and cell cycle progression. [7] Rho GTPases are central to dynamic actin cytoskeletal assembly and rearrangement that are the basis of cell-cell adhesion and migration. Activated Cdc42 activates by causing conformational changes [8] in p21-activated kinases PAK1 and PAK2, which in turn initiate actin reorganization and regulate cell adhesion, migration, and invasion. [9]
Cdc42 is a homodimer with A and B chains. [10] Its total length is 191 amino acids and its theoretical weight is 21.33 kDa. [10] Its sequence domains include a P-loop containing nucleoside triphosphate hydrolase and a small GTP-binding protein domain. [10]
Cdc42 cycles between an active GTP-bound state and an inactive GDP-bound state. This process is regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. [11]
Recently, Cdc42 has been shown to actively assist in cancer progression. Several studies have established the basis for this and hypothesized about the underlying mechanisms.
Cdc42 is overexpressed in non-small cell lung cancer, colorectal adenocarcinoma, melanoma, breast cancer, and testicular cancer. [12] Elevated levels of the protein have been correlated with negative patient survival. Cdc42 has also been shown to be required for both G1-S phase progression and mitosis, and it also modulates the transcription factors SRF, STAT3, and NFkB. [12] It has been hypothesized that targeting Cdc42 in conjunction with chemotherapy may be an effective cancer treatment strategy.
In one study studying the role of Cdc42 in cervical cancer, immunohistochemistry was used to detect Cdc42 expression in three types of tissues: normal cervical tissues, cervical intraepithelial neoplasia (CIN) I or below, CIN II or above, and cervical cancer tissues. [13] Cdc42 expression was gradually increased showing significant difference and was significantly higher in HeLa cells than in regular cells. The migration ability of HeLa cells transfected with Cdc42 was higher than that of non-transfected cells. [13] It was proposed that the overexpression of Cdc42 can promote filopodia formation in HeLa cells. Cdc42 overexpression significantly improved the ability of cervical cancer cells to migrate, possibly due to improved pseudopodia formation. [13]
Another study found that Cdc42 drives the process of initiating a metastatic tumor in a new tissue by promoting the expression of β1 integrin, an adhesion receptor known to be involved in metastasis. [14] Levels of β1 integrin were reduced in Cdc42-deficient cells. β1 integrin is important for adhesion to the extracellular matrix, and could be important for the initial attachment to endothelial cells as well. Knocking down β1 integrin inhibited cancer cell migration, whereas overexpressing the integrin in Cdc42-deficient cells restored endothelial invasion. [14] Cdc42 promoted β1 integrin expression by activating a transcription factor called SRF. A continually active form of the transcription factor was also capable of restoring endothelial insertion to cancer cells lacking Cdc42.
Normal cancer cells and Cdc42-deficient cancer cells have also been compared in vivo. When both types of cells were injected into mouse tail veins, control cells spread out more on the vessel endothelium within minutes, suggesting that Cdc42 assists in cell migration. [14] After six weeks, the control cells had generated more metastases than the Cdc42-deficient cells. Invading cancer cells send out protrusions that reach down between neighboring endothelial cells to contact the underlying basement membrane. The cancer cells then spread out on this extracellular matrix so that the endothelial cells retract, and allow the invaders to insert themselves between them. [14] In the absence of Cdc42, cancer cells failed to spread out on the basement membrane, and Cdc42-deficient cells showed reduced adhesion to extracellular matrix-coated coverslips. [14] Cdc42 therefore promotes the attachment of cancer cells to both endothelial cells and the underlying basement membrane during transendothelial migration.
The small molecular inhibitor AZA197 has been used to inhibit Cdc42 in the treatment of KRAS mutant colorectal cancers. [15] There was evidence that Cdc42 inhibition by AZA197 treatment suppresses proliferative and pro-survival signaling pathways via PAK1-ERK signaling and reduces colon cancer cell migration and invasion. [15] In mice, systemic AZA197 treatment in vivo reduced primary tumor growth and prolonged survival. [15] Therapy targeting Rho GTPase Cdc42 signaling pathways may be effective for treatment of patients with advanced colon cancer overexpressing Cdc42, and particularly those with KRAS-mutant disease.
Mutations in the CDC42 gene are responsible for the Takenouchi-Kosaki syndrome, an autosomal-dominant complex congenital developmental disorder associated with thrombocytopenia. [16] Alleic variants that are associated with the syndrome include mutations in the CDC42 gene that are expressed at the protein level as Ile21Thr, Tyr64Cys, Arg66Gly, Cys81Phe, Ser83Pro, or Glu171Lys. [17]
CDC42 has been shown to interact with:
The Wiskott–Aldrich syndrome protein (WASp) is a 502-amino acid protein expressed in cells of the hematopoietic system that in humans is encoded by the WAS gene. In the inactive state, WASp exists in an autoinhibited conformation with sequences near its C-terminus binding to a region near its N-terminus. Its activation is dependent upon CDC42 and PIP2 acting to disrupt this interaction, causing the WASp protein to 'open'. This exposes a domain near the WASp C-terminus that binds to and activates the Arp2/3 complex. Activated Arp2/3 nucleates new F-actin.
Ras-related C3 botulinum toxin substrate 1, is a protein that in humans 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.
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.
ROCK1 is a protein serine/threonine kinase also known as rho-associated, coiled-coil-containing protein kinase 1. Other common names are ROKβ and P160ROCK. ROCK1 is a major downstream effector of the small GTPase RhoA and is a regulator of the actomyosin cytoskeleton which promotes contractile force generation. ROCK1 plays a role in cancer and in particular cell motility, metastasis, and angiogenesis.
Rac GTPase-activating protein 1 is an enzyme that in humans is encoded by the RACGAP1 gene.
Rho guanine nucleotide exchange factor TIAM1 is a protein that in humans is encoded by the TIAM1 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.
Neural Wiskott–Aldrich syndrome protein is a protein that in humans is encoded by the WASL gene.
Ras-related protein Ral-A (RalA) is a protein that in humans is encoded by the RALA gene on chromosome 7. This protein is one of two paralogs of the Ral protein, the other being RalB, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers.
RhoC 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 RHOC.
Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ARHGEF7 gene.
A-kinase anchor protein 13 is a protein that in humans, is encoded by the AKAP13 gene. This protein is also called AKAP-Lbc because it encodes the lymphocyte blast crisis (Lbc) oncogene, and ARHGEF13/RhoGEF13 because it contains a guanine nucleotide exchange factor (GEF) domain for the RhoA small GTP-binding protein.
Rho guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the ARHGEF1 gene. This protein is also called RhoGEF1 or p115-RhoGEF.
Rho guanine nucleotide exchange factor 11 is a protein that in humans is encoded by the ARHGEF11 gene. This protein is also called RhoGEF11 or PDZ-RhoGEF.
Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene. This protein is also called RhoGEF12 or Leukemia-associated Rho guanine nucleotide exchange factor (LARG).
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.
Triple functional domain protein is a protein that in humans is encoded by the TRIO gene.
Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2. This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers.
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