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. [5] [6] This gene can produce a variety of alternatively spliced versions of the Rac1 protein, which appear to carry out different functions. [7]
Rac1 is a small (~21 kDa) signalling G protein (more specifically a GTPase), and is a member of the Rac subfamily of the family Rho family of GTPases. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of GLUT4 [8] [9] translocation to glucose uptake, cell growth, cytoskeletal reorganization, antimicrobial cytotoxicity, [10] and the activation of protein kinases. [11]
Rac1 is a pleiotropic regulator of many cellular processes, including the cell cycle, cell-cell adhesion, motility (through the actin network), and of epithelial differentiation (proposed to be necessary for maintaining epidermal stem cells).
Along with other subfamily of Rac and Rho proteins, they exert an important regulatory role specifically in cell motility and cell growth. Rac1 has ubiquitous tissue expression, and drives cell motility by formation of lamellipodia. [12] In order for cancer cells to grow and invade local and distant tissues, deregulation of cell motility is one of the hallmark events in cancer cell invasion and metastasis. [13] Overexpression of a constitutively active Rac1 V12 in mice caused a tumour that is phenotypically indistinguishable from human Kaposi's sarcoma. [14] Activating or gain-of-function mutations of Rac1 are shown to play active roles in promoting mesenchymal-type of cell movement assisted by NEDD9 and DOCK3 protein complex. [15] Such abnormal cell motility may result in epithelial mesenchymal transition (EMT) – a driving mechanism for tumour metastasis as well as drug-resistant tumour relapse. [16] [17]
Rac1 is expressed in significant amounts in insulin sensitive tissues, such as adipose tissue and skeletal muscle. Here Rac1 regulated the translocation of glucose transporting GLUT4 vesicles from intracellular compartments to the plasma membrane. [9] [18] [19] In response to insulin, this allows for blood glucose to enter the cell to lower blood glucose. In conditions of obesity and type 2 diabetes, Rac1 signalling in skeletal muscle is dysfunctional, suggesting that Rac1 contributes to the progression of the disease. Rac1 protein is also necessary for glucose uptake in skeletal muscle activated by exercise [8] [20] and muscle stretching [21]
Activating mutations in Rac1 have been recently discovered in large-scale genomic studies involving melanoma [22] [23] [24] and non-small cell lung cancer. [25] As a result, Rac1 is considered a therapeutic target for many of these diseases. [26]
A few recent studies have also exploited targeted therapy to suppress tumour growth by pharmacological inhibition of Rac1 activity in metastatic melanoma and liver cancer as well as in human breast cancer. [27] [28] [29] For example, Rac1-dependent pathway inhibition resulted in the reversal of tumour cell phenotypes, suggesting Rac1 as a predictive marker and therapeutic target for trastuzumab-resistant breast cancer. [28] However, given Rac1's role in glucose transport, drugs that inhibit Rac1 could potentially be harmful to glucose homeostasis.
Dominant negative or constitutively active germline RAC1 mutations cause diverse phenotypes that have been grouped together as Mental Retardation Type 48. [30] Most mutations cause microcephaly while some specific changes appear to result in macrocephaly.
RAC1 has been shown to interact with:
Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.
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.
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.
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.
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.
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 guanine nucleotide exchange factor 6 is a protein that, in humans, is encoded by the ARHGEF6 gene.
Dedicator of cytokinesis protein 1 (Dock1), also (DOCK180), is a large protein encoded in the human by the DOCK1 gene, involved in intracellular signalling networks. It is the mammalian ortholog of the C. elegans protein CED-5 and belongs to the DOCK family of guanine nucleotide exchange factors (GEFs).
Rho GDP-dissociation inhibitor 1 is a protein that in humans is encoded by the ARHGDIA gene.
Rho GDP-dissociation inhibitor 2 is a protein that in humans is encoded by the ARHGDIB gene. Aliases of this gene include RhoGDI2, GDID4, Rho GDI 2, and others.
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.
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.
Dedicator of cytokinesis protein 4 (Dock4), is a large protein encoded in the human by the DOCK4 gene, involved in intracellular signalling networks. It is a member of the DOCK-B subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock4 activates the small G proteins Rac and Rap1.
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