Signaling by Small GTPases in Metastatic Disease

The monomeric G-proteins, also termed as ‘small G-proteins’ or ‘small GTPases’ form an independent superfamily, the Ras superfamily, within the larger class of regulatory GTP hydrolases. These proteins switch between a GDP-bound inactive state to a GTP-bound active state and regulate various signal transduction cascades implicated in a multitude of cellular processes, including cell proliferation, differentiation, protein trafficking, cytoskeleton remodulation, and growth. The founder members of this superfamily, the RAS oncoprotein branch (HRAS, KRAS, and NRAS) are the best known for their oncogenic properties; the emerging evidence over several decades, however, now suggests that many of these small GTPases, their associated regulatory proteins and their effectors are the key components of various signal transduction pathways implicated in cancer. Deregulated signaling upstream of these molecules, together with aberrantly activated guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), determine their equilibrium between GTP- and GDP-bound forms and downstream signal relay.

Rap1A, one of the members of Ras family is known to regulate integrin-mediated cell adhesion and motility through its effectors. Rho family GTPases contribute to multiple cellular processes implicated in cancer progression, such as cytoskeletal dynamics, adhesion, polarity, motility, invasion, gene transcription, protein trafficking, cell cycle progression and survival. Ran small G proteins play important roles in controlling the nucleocytoplasmic transport of macromolecules, thus influence mitotic spindle assembly, nuclear envelope formation and cell cycle progression. Rab family GTPases are involved in coordination of the vesicle trafficking pathways in cancer. The members of another family, the ADP-ribosylation factor (Arf) family of small GTP-binding proteins have been found to be abnormally expressed in different cancer cell types and human cancers and seems to be regulating several aspects of membrane trafficking, such as vesicle budding, tethering and cytoskeleton organization.

All of these essential cellular functions wherein these small GTPases are known to be involved are exploited by cancer cells to disseminate and invade the tissues surrounding the primary tumor, leading to the formation of metastases. This issue of Frontiers in Cell and Developmental Biology focuses on signaling pathways mediated by these small GTPases in metastatic cancers and will provide further insight into their potential implications for novel drug targets to halt or slow disease progression, and for biomarkers to improve diagnostics and prognosis.