Cables1 Complex Couples Survival Signaling to the Cell Death Machinery

• Type of Material: Article
• Authors: Zhi Shi, Jinan University; Hae Ryon Park, Emory University; Yuhong Du, Emory University; Zijan Li, Emory University; Kejun Cheng, Emory University; Shi-Yong Sun, Emory University; Zenggang Li, Emory University; Haian Fu, Emory University; Fadlo Khuri, Emory University
• Language: English
• Date: 2015-01-01
• Publisher: AACR Publications
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-14-0036
• Title of Journal or Parent Work: Cancer Research
• Volume: 75
• Issue: 1
• Start Page: 147
• End Page: 158
• Grant/Funding Information: This work was supported by National Institutes of Health grants P01 CA116676 (to H.F. and F.R.K.), Georgia Cancer Coalition (to H.F. and F.R.K.), Winship Cancer Institute Kennedy Seed grant (Y.D), and following grants to Z.S.: the Chinese National Natural Science Foundation No. 31271444 and No. 81201726, the Foundation for Research Cultivation and Innovation of Jinan University No. 21612407, the Science and Technology Program of Guangzhou No. 14200010, and the Specialized Research Fund for the Doctoral Program of Higher Education No. 20124401120007.
• Keywords: Mediated Phosphorylation; Lung cancer; Cycle progression; Oncology; Chromosome 18Q; Science & Technology; Ovarian cancer; Cytoplasmic localization; Regulating kinase-1; Cancer progression; Life Sciences & Biomedicine; 14-3-3 Proteins; In-VIVO
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology; Chemistry, Biochemistry; Health Sciences, Pathology; Biology, Cell

Abstract

Cables1 is a candidate tumor suppressor that negatively regulates cell growth by inhibiting cyclin-dependent kinases. Cables1 expression is lost frequently in human cancer but little is known about its regulation. Here, we report that Cables1 levels are controlled by a phosphorylation and 14-3-3-dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex. In cells, Cables1 overexpression induced apoptosis and inhibited cell growth in part by stabilizing p21 and decreasing Cdk2 kinase activity. Ectopic expression of activated Akt (AKT1) prevented Cables1-induced apoptosis. Clinically, levels of phosphorylated Cables1 and phosphorylated Akt correlatedwith each other in human lung cancer specimens, consistent with pathophysiologic significance. Together, our results illuminated a dynamic regulatory system through which activated Akt and 14-3-3 work directly together to neutralize a potent tumor suppressor function of Cables1.