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Molecular and Cellular Biology, July 2003, p. 5090-5106, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.5090-5106.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Cdk5 Regulates the Organization of Nestin and Its Association with p35

Cecilia M. Sahlgren,1,2 Andrey Mikhailov,1,3 Samuli Vaittinen,4 Hanna-Mari Pallari,1 Hannu Kalimo,4 Harish C. Pant,5 and John E. Eriksson1,6*

Department of Biology, Åbo Akademi University, BioCity,2 Department of Pathology, Turku University Hospital, FIN-20520 Turku,4 Department of Biology, Laboratory of Animal Physiology, University of Turku, FIN-20014 Turku,6 Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FIN-20521 Turku, Finland,1 Cancer Research Center, Moscow 115478, Russia,3 Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 208925

Received 23 October 2002/ Returned for modification 4 December 2002/ Accepted 18 April 2003

The intermediate filament protein nestin is characterized by its specific expression during the development of neuronal and myogenic tissues. We identify nestin as a novel in vivo target for cdk5 and p35 kinase, a critical signaling determinant in development. Two cdk5-specific phosphorylation sites on nestin, Thr-1495 and Thr-316, were established, the latter of which was used as a marker for cdk5-specific phosphorylation in vivo. Ectopic expression of cdk5 and p35 in central nervous system progenitor cells and in myogenic precursor cells induced elevated phosphorylation and reorganization of nestin. The kinetics of nestin expression corresponded to elevated expression and activation of cdk5 during differentiation of myoblast cell cultures and during regeneration of skeletal muscle. In the myoblasts, a disassembly-linked phosphorylation of Thr-316 indicated active phosphorylation of nestin by cdk5. Moreover, cdk5 occurred in physical association with nestin. Inhibition of cdk5 activity—either by transfection with dominant-negative cdk5 or by using a specific cdk5 inhibitor—blocked myoblast differentiation and phosphorylation of nestin at Thr-316, and this inhibition markedly disturbed the organization of nestin. Interestingly, the interaction between p35, the cdk5 activator, and nestin appeared to be regulated by cdk5. In differentiating myoblasts, p35 was not complexed with nestin phosphorylated at Thr-316, and inhibition of cdk5 activity during differentiation induced a marked association of p35 with nestin. These results demonstrate that there is a continuous turnover of cdk5 and p35 activity on a scaffold formed by nestin. This association is likely to affect the organization and operation of both cdk5 and nestin during development.

* Corresponding author. Mailing address: Department of Biology, University of Turku, FIN-20014 Turku, Finland. Phone: 358-2-333-8036. Fax: 333-2-333-8000. E-mail: john.eriksson{at}utu.fi.

Molecular and Cellular Biology, July 2003, p. 5090-5106, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.5090-5106.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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