Mammalian Cdk5 is a functional homologue of the budding yeast Pho85 cyclin-dependent protein kinase

Mammalian Cdk5 is a member of the cyclin-dependent kinase family that is ac tivated by a neuron-specific regulator, p35. to regulate neuronal migration and neurite outgrowth. p35/Cdk5 kinase colocalizes with and regulates the activity of the Pak1 kinase in neuronal growth cones and likely impacts on actin cytoskeletal dynamics through Pak1. Here, we describe a functional ho mologue of Cdk5 in budding yeast. Pho85. Like Cdk5. Pho85 has been implicat ed in actin cytoskeleton regulation through phosphorylation of an actin-reg ulatory protein. Overexpression of CDK5 in yeast cells complemented most ph enotypes associated with pho85 Delta, including defects in the repression o f acid phosphatase expression, sensitivity to salt, and a G(1) progression defect. Consistent with the functional complementation. Cdk5 associated wit h and was activated by the Pho85 cyclins Pho80 and Pcl2 in yeast cells. In a reciprocal series of experiments, we found that Pho85 associated with the Cdk5 activators p35 and p25 to form an active kinase complex in mammalian and insect cells, supporting our hypothesis that Pho85 and Cdk5 are functio nally related. Our results suggest the existence of a functionally conserve d pathway involving Cdks and actin-regulatory proteins that promotes reorga nization of the actin cytoskeleton in response to regulatory signals.