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Regulation of the CDK-related protein kinase PCTAIRE-1 and its possible role in neurite outgrowth in Neuro-2A cells

Ralph Graeser^1,*,, Julian Gannon¹, Randy Y. C. Poon², Thierry Dubois^3,, Alastair Aitken³ and Tim Hunt¹

¹ ICRF Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK
² Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
³ Division of Biomedical and Clinical Laboratory Sciences, Section of Biomedical Sciences, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
^* Present address: Target Identification and Validation, ProQinase GmbH, Breisacher Str. 117, D-79106 Freiburg, Germany
Present address: Institut Curie — Section Recherche, CNRS UMR 144, 26 rue d'Ulm, 75248 Paris Cedex 05, France

Author for correspondence (e-mail: r.graeser{at}proqinase.com)

Accepted 12 June 2002

PCTAIRE-1 is a CDK-related protein kinase found in terminally differentiated cells in brain and testis, and in many immortalised and transformed cell lines. Bacterially expressed PCTAIRE is completely inactive as a protein kinase, but is a very good substrate for protein kinase A (PKA), which phosphorylates a total of four sites in the N-terminus of PCTAIRE-1. Phosphorylation of one of these sites, Ser119, generates a 14-3-3 binding site, which is functional in vitro as well as in vivo. Mutation of another PKA site, Ser153, to an alanine residue generated an activated kinase in transfected mammalian cells. This activity was comparable to that of CDK5 activated by a bacterially expressed, truncated version of p35^nck, p21. Gel filtration analysis of a brain extract suggested that monomeric PCTAIRE-1 was the active species, implying that PCTAIRE-1 may not be a true CDK, in that it does not require a partner (cyclin-like) subunit for kinase activity. Finally, we found that various forms of PCTAIRE-1 transfected into neuroblastoma cell lines could either promote or inhibit neurite outgrowth, suggesting a potential role for the PCTAIRE-1 gene product in the control of neurite outgrowth.

Key words: PCTAIRE-1, CDK-related, Protein kinase A, 14-3-3, Neurite outgrowth

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