Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIB gene. [5] [6] [7] Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others. [8]
Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIB gene. [5] [6] [7] Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others. [8]
ARHGDIB has been shown to interact with VAV1 [9] and Src. [10]
RhoGDI2 (ARHGDIB) is part of a family of three members: RhoGDI1, RhoGDI2 (also known as RhoGDIB, D4-GDI or Ly-GDI) and RhoGDI3. RhoGDI1 is expressed in many organs and is the best studied member of the family. [11] [12] [13] RhoGDI2 was initially believed to be expressed specifically in blood forming cells, [6] but has subsequently been found to be highly expressed in a variety of other cell types as well. [14] RhoGDI3 is predominantly expressed in brain, lung, kidney, testis and pancreas, [15] [16] and is targeted to specific parts of the cell such as the Golgi where it may play a role in transport or proteins in cells. [17] [18]
Despite a high degree of sequence similarity, RhoGDI1 and RhoGDI2 are very different in their binding affinities for specific GTPases, [19] and more importantly, in their roles in tumor formation and spread of tumor to other organs (the process of metastasis). [20] For example, RhoGDI2 functions as a suppressor of metastasis but not a tumor suppressor in bladder cancer cells, [14] [21] while RhoGDI1 is a ubiquitous suppressor of tumor growth in all sites so far examined in bladder cancer models), [22] suggesting that their cellular functions must diverge to cause these differential effects.
While there are clear links between the alteration of RhoGDI2 protein levels and disease progression and/or metastasis in several types of cancer, the mechanistic underpinnings of the mode of RhoGDI2 action under carcinogenic cellular conditions are only now beginning to be understood. Evidence demonstrates that RhoGDI2 inhibits the endothelin axis and crosstalk with macrophages within the micrometastatic microenvironment to inhibit metastatic outgrowth. [23] As such, RhoGDI2 could prove important in the regulation of tumor dormancy. Targeting this axis with orally available endothelin receptor antagonists [24] may prove efficacious in mimicking the inhibitory role of RhoGDI2 by preventing macrophage infiltration into the micrometastatic niche. [25] Recent work has also determined that genetic and pharmacologic targeting of chemokine (C-C motif) ligand 2 (CCL2) also known as monocyte chemotactic protein-1 (MCP-1) or small inducible cytokine A2, its receptor CCR2 and pharmacologic ablation of macrophages can also phenocopy the effect of RhoGDI2 expression to prevent metastatic colonization of the lung67 and that RhoGDI2 is suppressor of versican, a protein that has been shown to promote cell migration [26] and metastasis in several tumor models.
In contrast to its role as a metastasis suppressor in bladder cancer, in breast, RhoGDI2 expression has been reported to be upregulated in cancer [27] and to promote invasion of breast cancer cells, [28] while another report found a biphasic expression pattern of RhoGDI2 in breast cancer with decreased expression correlating with lymph node metastasis. [29]
ARHGDIB antibodies may be a marker for long-term kidney graft loss in recipients of deceased-donor kidneys. [30]
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.
Small GTPases, also known as small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.
The Rab family of proteins is a member of the Ras superfamily of small G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab proteins generally possess a GTPase fold, which consists of a six-stranded beta sheet which is flanked by five alpha helices. Rab GTPases regulate many steps of membrane trafficking, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface.
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.
In molecular biology, the Guanosine dissociation inhibitors (GDIs) constitute a family of small GTPases that serve a regulatory role in vesicular membrane traffic. GDIs bind to the GDP-bound form of Rho and Rab small GTPases and not only prevent exchange, but also prevent the small GTPase from localizing at the membrane, which is their place of action. This inhibition can be removed by the action of a GDI displacement factor. GDIs also inhibit cdc42 by binding to its tail and preventing its insertion into membranes; hence it cannot trigger WASPs and cannot lead to nucleation of F-actin.
The Rho family of GTPases is a family of small signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are "molecular switches", and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions.
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.
Ras homolog gene family, member B, also known as RHOB, is a protein which in humans is encoded by the RHOB 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.
Rab GDP dissociation inhibitor alpha is a protein that in humans is encoded by the GDI1 gene.
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.
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 GDP-dissociation inhibitor 1 is a protein that in humans is encoded by the ARHGDIA gene.
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.
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.
Rab GDP dissociation inhibitor beta is a protein that in humans is encoded by the GDI2 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.
A metastasis suppressor is a protein that acts to slow or prevent metastases from spreading in the body of an organism with cancer. Metastasis is one of the most lethal cancer processes. This process is responsible for about ninety percent of human cancer deaths. Proteins that act to slow or prevent metastases are different from those that act to suppress tumor growth. Genes for about a dozen such proteins are known in humans and other animals.
Rho GDP-dissociation inhibitor 3 is a protein that in humans is encoded by the ARHGDIG gene.
Dan Theodorescu is an American physician and academic. He is the Director of the Samuel Oschin Comprehensive Cancer Institute at the Cedars-Sinai Medical Center and leader of Cedars-Sinai CANCER. From 2010 until 2018, Theodorescu was Director of the University of Colorado Cancer Center and a professor of Surgery-Urology. He has been appointed Paul Mellon Chair at the University of Virginia and Paul Bunn Chair and Distinguished University Professor at the University of Colorado.
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