Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.
Nat Commun. 2013;4:1618. 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.
肝癌缺失基因 1（DLC1）是一种肿瘤抑制因子，它编码一种 RhoGTPase 激活蛋白（RhoGAP），并且在许多人类癌症中经常失活。DLC1 针对 Rho 信号的 RhoGAP 活性已有充分的记录，并且与 DLC1 的肿瘤抑制功能密切相关。然而，DLC1 的 RhoGAP 活性是如何被调节的机制仍然不清楚。在这里，我们报告说，环腺苷酸依赖性蛋白激酶 A（PKA）对 DLC1 的 Ser549 进行磷酸化有助于增强 RhoGAP 活性，并促进 DLC1 的激活，从而抑制肝癌细胞在体外和体内模型中的生长、迁移和转移。有趣的是，我们发现 Ser549 磷酸化诱导 DLC1 的二聚化，并且 DLC1 的诱导二聚化可以挽救含有 Ser549 缺失的 DLC1 的肿瘤抑制和 RhoGAP 活性。我们的研究建立了一种通过蛋白激酶 A 信号诱导的二聚化来调节 DLC1 RhoGAP 活性的新机制。
