RhoC (Ras homolog gene family, member C) is a small (~21 kDa) signaling

G protein 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 act ...

(more specifically a

GTPase 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 is a member of the Rac subfamily of the family

Rho family of GTPases The Rho family of GTPases is a family of small (~21 kDa) 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 ...

. It is encoded by the gene RHOC.

Mechanism and function

It is prenylated at its

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. It cycles between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape and motility. RhoC can activate formins such as mDia1 and FMNL2 to remodel the cytoskeleton. Overexpression of RhoC is associated with cell proliferation and causing tumors to become malignant. It causes degradation and reconstruction of the Extracellular Matrix (ECM) which helps cells escape the tissue they are currently in. It enhances cell motility giving it the ability to become invasive. It has been found to have a direct relationship to advanced tumor stage and metastasis, with increases in stage being related to increases in RhoC expression. RhoC-deficient mice can still develop tumors but these fail to metastasize, arguing that RhoC is essential for metastasis. It has also been found to enhance the creation of angiogenic factors such as VEGF, which is necessary for a tumor to become malignant. In a study by Vega, RhoC was knocked out which resulted in cells spreading out wide in all directions. When RhoC was disabled, the cell's abilities to move in a specific direction and migrate was impaired. It also reduced the cell's speed of movement, because it was difficult, and sometimes impossible, to polarize the cell.

Associated Signaling Pathways

RhoC expression has been associated with several signaling pathways and effectors. Here is a list of the ones found so far: * IQGAP1 (IQ-domain GTP-ase Activating Protein): an effector of RhoC to enhance expression of cyclin E and cyclin D1. This resulted in cells being promoted to enter S phase more rapidly * ROCK-1 * MMP9: necessary for ECM regulation * FMNL3: a Formin downstream target, which is used to regulate where Rac1 is active * MAPK pathway: upregulating VEGF, Basic fibroblastic growth factors, and interleukins 6 and 8 expression * Notch1 * PI3K/AKt pathway: Proliferation and invasiveness * Pyk2: metastasis

Types of Cancer RhoC has been studied in

RhoC has been found to be overexpressed in: * Lung Cancer * Gastric Cancer * Ovarian cancer * Breast Cancer * Hepatocellular Cancer * Pancreatic Cancer * Colorectal Cancer * Cancer of the Urogenital System * Melanoma * Prostate Cancer * Cervical Carcinoma

Potential Therapies

RhoC small interfering RNA (siRNA) have been used in studies to successfully inhibit proliferation of some invasive cancers RhoC can be used as a biomarker for judging the metastatic potential of tumors One study used "recombinant adenovirus mediated RhoC shRNA in tandem linked expression" to successfully inhibit RhoC It has been found that RhoC expression is not important for embryogenesis but it is only important for metastasis, which would make it a good target for treatments. A RhoC targeted therapy (RV001 by RhoVac) is currently tested in prostate cancer in an ongoing clinical phase 2b program in the US and Europe. Results are expected mid 2022 (Reference: https://clinicaltrials.gov/ct2/show/NCT04114825)

References

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