Regulation of deleted in liver cancer 1 tumor suppressor by protein-protein interactions and phosphorylation

摘要

The deleted in liver cancer 1 (DLC1) tumor suppressor is an important RhoGTP activating protein (RhoGAP) that plays a crucial role in many types of human cancers. Small GTPases regulate normal cellular processes but aberrant expression and activation of GTPases contribute to tumorigenesis. RhoGAP suppresses Rho activity. DLC1's RhoGAP activity and the focal adhesion localization are critical to the tumor suppressor functions of DLC1. Frequent DLC1 underexpression is commonly seen in human cancers and has been ascribed to genomic deletion and epigenetic inactivation. Somatic mutation has been shown to deregulate the RhoGAP activity of DLC1. Deregulation of DLC1 in cells results in the elevation of active Rho. Compelling studies of the molecular mechanisms of DLC1 action have identified various interacting partners of DLC1 such as tensins and caveolin-1, and revealed the associated signaling pathways. DLC1 has been shown to be a promiscuous interacting protein. Recent interest has also focused on the phosphorylation of DLC1. The upstream kinases such as PKA, PKB/Akt and PKC, and the effects of phosphorylation on the biological activities of DLC1 have been demonstrated. Although DLC1 is a RhoGAP, RhoGAP-independent pathways have been involved via its interacting partners and upon phosphorylation regulation. Recent studies of DLC1 point to the complexity of the signaling pathways it regulates. This review summarizes the current understanding of the interacting potentials of DLC1 and phosphorylation of DLC1.