Ko, F. C. F., Chan, L. K., Tung, E. K. K., Lowe, S. W., Ng, I. O. L., Yam, J. W. P. (October 2010) Akt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis. Gastroenterology, 139 (4).
Abstract
Background & Aims Deleted in liver cancer 1 (DLC1), which encodes a Rho GTPase activating protein, is a bona fide tumor suppressor in hepatocellular carcinoma. Underexpression of DLC1 in cancer has been attributed to genomic deletion and epigenetic silencing. However, the regulatory mechanism of the tumor suppressive activity of DLC1 remains elusive. In this study, we elucidated a novel post-translational modification by which the activity of DLC1 is functionally regulated. Methods Molecular and biochemical approaches were employed to study Akt phosphorylation of DLC1. In vitro and in vivo functional assays were performed to elucidate the functional significance of Akt phosphorylation of DLC1. Results Phosphorylation of ectopically expressed and endogenous DLC1 was enhanced upon insulin induction or with Akt expression in liver cancer cell lines. Conversely, addition of a phosphatidylinositol 3-kinase/Akt pathway inhibitor or silencing of Akt attenuated the phosphorylation level of DLC1. Site-directed mutagenesis was employed to replace the serine residue of the consensus Akt substrate motifs of DLC1 with alanine. S567 of DLC1 was identified as the only target of Akt phosphorylation. S567 is well conserved in all DLC family members. DLC2 was phosphorylated by Akt at the corresponding residue. Functional assays demonstrated that the S567D phosphomimetic DLC1 mutant lost its inhibitory activities in tumorigenesis and metastasis of oncogenically transformed hepatoblasts in a mouse model. Conclusions This study has revealed a novel post-translational modification that functionally deregulates the biologic activities of DLC1. Phosphorylation of DLC1 and DLC2 by Akt at the conserved residue points to a common regulatory mechanism of the DLC tumor suppressor family. © 2010 AGA Institute.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Akt Deleted in Liver Cancer 1 Hepatocellular Carcinoma Phosphorylation |
| Subjects: | diseases & disorders > cancer > cancer types > liver cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab |
| Depositing User: | CSHL Librarian |
| Date: | October 2010 |
| Date Deposited: | 03 Oct 2011 20:52 |
| Last Modified: | 08 Mar 2018 16:15 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/15456 |
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