title: Cables1 complex couples survival signaling to the cell death machinery.
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 correlated with 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.
authors.affiliation: Department of Cell Biology & Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.|Department of Pharmacology, Emory University, Atlanta, Georgia 30322.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia 30322.|Department of Oral Pathology, School of Dentistry, Pusan National University, Pusan, South Korea.
authors.forename: Hae Ryon
authors.initials: HR
authors.lastname: Park
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia 30322.|Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia 30322.|Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
authors.forename: Zijian
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia 30322.|Chemical Biology Center, Lishui Institute of Agricultural Sciences, Lishui, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Department of Hematology & Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322.
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia 30322.
authors.forename: Zenggang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, Georgia 30322.|Department of Hematology & Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322.|Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Hematology & Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322.|Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D002522:Chlorocebus aethiops; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D048948:14-3-3 Proteins; C486568:CABLES1 protein, human; D002352:Carrier Proteins; D016213:Cyclins; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt