Cyclin-dependent kinase 5 (Cdk5) is a small serine/threonine kinase that plays a pivotal role during development of the CNS. Cables, a novel protein, interacts with Cdk5 in brain lysates. Cables also binds to and is a substrate of the c-Abl tyrosine kinase. Active c-Abl kinase leads to Cdk5 tyrosine phosphorylation, and this phosphorylation is enhanced by Cables. Phosphorylation of Cdk5 by c-Abl occurs on tyrosine 15 (Y15), which is stimulatory for p35/Cdk5 kinase activity. Expression of antisense Cables in primary cortical neurons inhibited neurite outgrowth. Furthermore, expression of active Abl resulted in lengthening of neurites. The data provide evidence for a Cables-mediated interplay between the Cdk5 and c-Abl signaling pathways in the developing nervous system.
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The authors would like to thank Yolande Ramos and Shih-Te Wen for DNA constructs and technical support; Ming Sum Lee, Vivien Tannoch, Young Kwon, Deanna Smith, and Elena Porro for help in preparation of this manuscript; and members of the Tsai laboratory for helpful discussions. L. Lanier is supported by the Anna Fuller Fund, and F. Gertler is supported by Merck and Company. This work was supported in part by National Institutes of Health grant RO1-NS37007 (to L.-H. T.). L.-H. T. is an assistant investigator of the Howard Hughes Medical Institute, a Rita Allen Foundation scholar, and a recipient of an Esther A. and Joseph Klingenstein Foundation Fund.