PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

• Published in: Nature communications Vol. 4; no. 1; p. 1618
• Main Authors: Ko, Frankie Chi Fat, Chan, Lo-Kong, Man-Fong Sze, Karen, Yeung, Yin-Shan, Yuk-Ting Tse, Edith, Lu, Ping, Yu, Ming-Hua, Oi-Lin Ng, Irene, Yam, Judy Wai Ping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group
• Subjects: 631/67; 631/80/86; Animals; Cell Transformation, Neoplastic; Cyclic AMP-Dependent Protein Kinases - metabolism; Dimerization; GTPase-Activating Proteins - chemistry; GTPase-Activating Proteins - physiology; HEK293 Cells; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Neoplasm Metastasis; Phosphorylation; Science; Science (multidisciplinary); Transplantation, Heterologous; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2604

Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that encodes a RhoGTPase-activating protein (RhoGAP) and is frequently inactivated in many human cancers. The RhoGAP activity of DLC1 against Rho signalling is well documented and is strongly associated with the tumour suppressor functions of DLC1. However, the mechanism by which the RhoGAP activity of DLC1 is regulated remains obscure. Here, we report that phosphorylation of DLC1 at Ser549 by cyclic AMP-dependent protein kinase A contributes to enhanced RhoGAP activity and promotes the activation of DLC1, which suppresses hepatoma cell growth, motility and metastasis in both in vitro and in vivo models. Intriguingly, we found that Ser549 phosphorylation induces the dimerization of DLC1 and that inducible dimerization of DLC1 can rescue the tumour suppressive and RhoGAP activities of DLC1 containing a Ser549 deletion. Our study establishes a novel regulatory mechanism for DLC1 RhoGAP activity via dimerization induced by protein kinase A signalling. Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that inhibits metastasis by inactivating the small GTPase, RhoA. Here the authors reveal that DLC1 function is stimulated by protein kinase A, which induces phosphorylation-dependent DLC1 dimerization.