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

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

^*Department of Molecular and Medical Genetics, University of Toronto, 1 Kings College Circle, Toronto, Canada M5S 1A8; and ^†Howard Hughes Medical Institute and Department of Pathology, Harvard Medical School, Boston, MA 02115

Edited by Ira Herskowitz, University of California, San Francisco, CA, and approved October 13, 1999 (received for review May 26, 1999)

Abstract

Mammalian Cdk5 is a member of the cyclin-dependent kinase family that is activated 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 homologue of Cdk5 in budding yeast, Pho85. Like Cdk5, Pho85 has been implicated in actin cytoskeleton regulation through phosphorylation of an actin-regulatory protein. Overexpression of CDK5 in yeast cells complemented most phenotypes associated with pho85Δ, including defects in the repression of acid phosphatase expression, sensitivity to salt, and a G₁ progression defect. Consistent with the functional complementation, Cdk5 associated with 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 functionally related. Our results suggest the existence of a functionally conserved pathway involving Cdks and actin-regulatory proteins that promotes reorganization of the actin cytoskeleton in response to regulatory signals.

Footnotes

↵ ‡ To whom reprint requests should be addressed. E-mail: brenda.andrews{at}utoronto.ca.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Cdk,

cyclin-dependent kinase;

Pcl,

Pho85 cyclin;

HA,

hemagglutinin;

GST,

glutathione S-transferase