Cyclin-dependent Kinase-5 Is Involved in Neuregulin-dependent Activation of Phosphatidylinositol 3-Kinase and Akt Activity Mediating Neuronal Survival

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5–/–mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays an important role in mediating survival signals in wide variety of neurons and cells. Recent studies show that Akt also regulates metabolic pathways to regulate cell survival. In this study, we reported that cyclin-dependent kinase-5 (Cdk5) regulates Akt activity and cell survival through the neuregulin-mediated PI 3-kinase signaling pathway. We found that brain extracts of Cdk5–/–mice display a lower PI 3-kinase activity and phosphorylation of Akt compared with that in wild type mice. Moreover, we demonstrated that Cdk5 phosphorylated Ser-1176 in the neuregulin receptor ErbB2 and phosphorylated Thr-871 and Ser-1120 in the ErbB3 receptor. We identified the Ser-1120 sequence RSRSPR in ErbB3 as a novel phosphorylation consensus sequence of Cdk5. Finally, we found that Cdk5 activity is involved in neuregulin-induced Akt activity and neuregulin-mediated neuronal survival. These findings suggest that Cdk5 may exert a key role in promoting neuronal survival by regulating Akt activity through the neuregulin/PI 3-kinase signaling pathway. Cyclin-dependent kinase 5 (Cdk5) 1The abbreviations used are: Cdk5, cyclin-dependent kinase-5; NRG, neuregulin; PI3K, phosphatidylinositol 3-kinase; HA, hemagglutinin; PBS, phosphate-buffered saline; MALDI-TOF, matrix-assisted laser desorption/ionization time-of-flight; PtdIns(4,5)P2, phosphatidylinositol 4,5-diphosphate; PtdIns(3,4,5)P3, phosphatidylinositol 3,4,5-trisphosphate; PDK1, phosphoinositide-dependent kinase-1; IP, immunoprecipitation; E18, embryonic day 18; TUNEL, terminal deoxynucleotidyl-transferase enzyme-mediated dUTP nick end labeling. is a serine/threonine kinase, which is predominantly expressed in postmitotic neurons (1Hellmich M.R. Pant H.C. Wada E. Battey J.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10867-10871Crossref PubMed Scopus (248) Google Scholar). Cdk5 kinase activity requires association with its neuron-specific activators, p35 and p39. Cdk5 kinase activity is essential for neuronal migration, neurite outgrowth, and laminar configuration of the cerebral cortex (2Lew J. Huang Q.Q. Qi Z. Winkfein R.J. Aebersold R. Hunt T. Wang J.H. Nature. 1994; 371: 423-426Crossref PubMed Scopus (545) Google Scholar, 3Tsai L.H. Delalle I. Caviness Jr., V.S. Chae T. Harlow E. Nature. 1994; 371: 419-423Crossref PubMed Scopus (818) Google Scholar, 4Humbert S. Dhavan R. Tsai L-H. J. Cell Sci. 2000; 113: 975-983Crossref PubMed Google Scholar). Recently, Cdk5 has been suggested as contributing to the control of neuronal positioning in Reelin signaling during neural development (5Ohshima T. Mikoshiba K. Mol. Neurobiol. 2002; 26: 153-166Crossref PubMed Scopus (41) Google Scholar) and to mediate neuronal guidance by regulating semaphorin-3A with Fyn kinase (6Sasaki Y. 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Acad. Sci. U. S. A. PubMed Scopus Google and the of and In this study, we that Cdk5 regulates Akt activity through phosphorylation of the neuregulin and of kinase signaling We found that brain extracts and neurons Cdk5 knockout mice and increased The Ser-1120 in the RSRSPR sequence in the ErbB3 receptor is a novel Cdk5 consensus we that Cdk5 activity neuronal survival by a at the receptor Cell neurons embryonic day and Cdk5 wild type and knockout mice as by Li B.S. Zhang L. Takahashi S. Ma W. H. Kulkarni A.B. Pant H.C. EMBO J. 2002; 21: PubMed Scopus Google Scholar). In and with The by and in a with and Cells in with for and in with of of and wild type mice with phosphate-buffered and in a 5 and The at for The for in phosphorylation and of of and wild type mice brain phosphorylated as by Li B.S. Zhang L. Takahashi S. Ma W. H. Kulkarni A.B. Pant H.C. EMBO J. 2002; 21: PubMed Scopus Google Scholar). 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Biol. 1997; Full Text Full Text PDF PubMed Google we compared the Akt phosphorylation and activity in extracts of type and mice and The Akt and phosphorylated Akt expression by with and Akt Akt kinase activity brain extracts with Akt and as a We found that expression of Akt protein of wild type and mice the phosphorylation of Akt and its activity in the mice compared with wild type brain extracts and the Akt activity to in mice brain the Akt phosphorylation and may be to of used in In the of Cdk5 activity in the that Cdk5 ErbB3 and ErbB2 by suggest that Cdk5 activity is involved in the signaling pathway. the for Cdk5, we the that the is implicated in neuregulin-induced acetylcholine receptor expression at the neuromuscular junction (13Fu A.K. Fu W.Y. Cheung J. Tsim K.W. Ip F.C. Wang J.H. Ip N.Y. Nat. 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A. 1997; 94: 9562-9567Crossref PubMed Scopus (334) Google Scholar). exhibit in and increased apoptosis that with activity (16Gao C. Negash S. Wang H.S. Ledee D. Guo H. Russell P. Zelenka P. J. Cell Sci. 2001; 114: 1145-1153PubMed Google Scholar). Finally, in neurodegenerative it has been suggested that of Cdk5 activity by of p35 to with neuronal in Alzheimer's disease (18Patrick G.N. Zukerberg L. Nikolic M. de la Monte S. Dikkes P. Tsai L.H. Nature. 2001; 411: 764-765Crossref PubMed Scopus (17) Google Scholar). On the other hand, a of studies in to the reported show that Cdk5 is involved in cell survival. The of Cdk5 activity in the Cdk5 knockout and and and increased apoptosis T. M. G. Pant H.C. Kulkarni A.B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, B.S. Zhang L. Takahashi S. Ma W. H. Kulkarni A.B. Pant H.C. EMBO J. 2002; 21: PubMed Scopus Google Scholar). 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