Rho GDP-dissociation inhibitor 2 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''ARHGDIB''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Aliases of this gene include ''RhoGDI2'', ''GDID4'', ''Rho GDI 2'', and others.
Interactions
ARHGDIB has been shown to
interact with
VAV1
Proto-oncogene vav is a protein that in humans is encoded by the ''VAV1'' gene.
Function
The protein encoded by this proto-oncogene is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding ...
and
Src.
Gene family
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.
RhoGDI2 was initially believed to be expressed specifically in blood forming cells,
but has subsequently been found to be highly expressed in a variety of other cell types as well.
RhoGDI3 is predominantly expressed in brain, lung, kidney, testis and pancreas,
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.
Disease involvement
Despite a high degree of sequence similarity, RhoGDI1 and RhoGDI2 are very different in their binding affinities for specific
GTPases
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 pro ...
,
and more importantly, in their roles in tumor formation and spread of tumor to other organs (the process of
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
).
For example, RhoGDI2 functions as a suppressor of metastasis but not a
tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
in
bladder cancer
Bladder cancer is the abnormal growth of cells in the bladder. These cells can grow to form a tumor, which eventually spreads, damaging the bladder and other organs. Most people with bladder cancer are diagnosed after noticing blood in thei ...
cells,
while RhoGDI1 is a ubiquitous suppressor of tumor growth in all sites so far examined in bladder cancer models),
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
Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...
axis and crosstalk with
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s within the
micrometastatic microenvironment to inhibit metastatic outgrowth.
As such, RhoGDI2 could prove important in the regulation of tumor dormancy. Targeting this axis with orally available endothelin receptor antagonists
may prove efficacious in mimicking the inhibitory role of RhoGDI2 by preventing macrophage infiltration into the micrometastatic niche.
Recent work has also determined that genetic and pharmacologic targeting of chemokine (C-C motif) ligand 2 (
CCL2
The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL2 is a small cytokine that belongs to the CC chemokine family. CCL2 tightly regulates cellular mecha ...
) 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
Versican is a large extracellular matrix proteoglycan that is present in a variety of human tissues. It is encoded by the ''VCAN'' gene.
Versican is a large chondroitin sulfate proteoglycan with an apparent molecular mass of more than 1000kDa. I ...
, a protein that has been shown to promote cell migration
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
and to promote invasion of breast cancer cells,
while another report found a biphasic expression pattern of RhoGDI2 in breast cancer with decreased expression correlating with lymph node metastasis.
ARHGDIB antibodies may be a marker for long-term kidney graft loss in recipients of deceased-donor kidneys.
References
Further reading
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External links
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{{PDB Gallery, geneid=397
Genes
Human proteins