What is Small Gtpase Super Family?
Small Gtpase Super Family, a GTP-binding protein family, is ubiquitous in eukaryotic cells. Small GTPases exist as monomers which function as molecular switches in intracellular signaling to control a wide variety of cellular functions. The small GTPase ADP-ribosylation factor 6 (Arf6) plays important roles in a wide variety of membrane dynamics-based cellular events such as neurite outgrowth and spine formation in vitro.
Ras, a subfamily of the Small Gtpase Super Family, functions as molecular switches by undergoing nucleotide-dependent conformational exchange. When GTP-bound, RAS GTPases are bound directly by effector proteins that are responsible for transmitting signals to diverse cellular pathways. AFDN/Afadin is required for establishment and maintenance of cell-cell contacts and is a unique effector of RAS GTPases. The dual RA domains of AFDN have broad specificity for RAS and RAP GTPases, and KRAS co-localizes with AFDN and promotes AFDN-SCRIB complex formation. Knockout of AFDN or SCRIB in epithelial cells disrupts MAPK and PI3K activation kinetics and inhibits motility in a growth factor-dependent manner. The above mechanism have important implications for understanding why AFDN as an effector activated RAS have reduced cell contacts and polarity defects.
Fig 1 Activation of RAS subfamily small GTPases is governed by differential binding to guanine nucleotides.
In the GTP-bound state RAS interacts with effector proteins, including AFDN.
Rho, a subfamily of the Small Gtpase Super Family, ubiquitous in yeast cells and most animal cells, regulates epithelial adhesion and polarity, cell migration, membrane traffic, and the cell division cycle. Rho GTPase Rnd1 Rho GTPase Rnd1 has been shown to be a candidate metastasis suppressor in triple-negative breast cancer. Depletion of Rnd1 disrupted epithelial adhesion and polarity, induced epithelial-to-mesenchymal transition, and cooperated with deregulated expression of c-Myc or loss of p53 to cause neoplastic conversion. Rnd1 suppresses Ras signalling by activating the GAP domain of Plexin B1, which inhibits Rap1. Rap1 inhibition in turn led to derepression of p120 Ras-GAP, which was able to inhibit Ras. Therefore, based on the mechanism by which RND1 inhibits the development of breast cancer by inhibiting RAS-MAPK signaling, the study of Rnd1 will help us to find effective drug therapeutic targets for breast cancer.
Fig 2 Mechanistic model showing Rnd1-dependent regulation of Ras
activation through Rap-mediated interaction of p120 Ras-GAP
Rab, the largest branch of the Small GTPase Super Family, interacts with effector proteins that control downstream signaling in their GTP-bound (active) form. Rab GTPases have defined membrane locations and mediate the exchange of cargos between different organelles via selective binding and recruiting of distinct Rab interacting proteins. In the GTP-bound form, Rab is in an active state (on) and GDP-bound Rab is inactive (off). Guanine nucleotide exchange factors (GEFs) catalyze exchange of GDP by GTP and GTPase activating proteins (GAPs) that deactivate Rab by increasing the rate of GTP hydrolysis. Rab will be an important target in the treatment of some diseases. For example, Rab3 paralogs have been implicated in various cancers.
Small Gtpase Super Family, the important protein family of yeast cells and most animal cells, are major targets for drug discovery, which provides a new research idea for drug intervention therapy of cancers.