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Vol. 12, No. 4-5, 2003
Issue release date: September–October 2003
Section title: Review
Neurosignals 2003;12:221–229
(DOI:10.1159/000074624)

The Regulation of Cyclin-Dependent Kinase 5 Activity through the Metabolism of p35 or p39 Cdk5 Activator

Hisanaga S.-i. · Saito T.
Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan

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Article / Publication Details

First-Page Preview
Abstract of Review

Received: 7/4/2003
Accepted: 9/5/2003
Published online: 12/18/2003

Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 0

ISSN: 1424-862X (Print)
eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG

Abstract

Cyclin-dependent kinase 5 (Cdk5) displays kinase activity predominantly in post-mitotic neurons and its physiological roles are unrelated to cell cycle progression. Cdk5 is activated by its binding to a neuron-specific activator, p35 or p39. The protein amount of p35 or p39 is a primary determinant of the Cdk5 activity in neurons, with the amount of p35 or p39 being determined by its synthesis and degradation. The expression of p35 is induced in differentiated neurons and is enhanced by extracellular stimuli such as neurotrophic factors or extracellular matrix molecules, specifically those acting on the ERK/Erg pathway. p35 is a short-lived protein and its degradation determines the life span. Degradation is mediated by the ubiquitin/proteasome system, similar to that for cyclins in proliferating cells. Autophosphorylation of p35 by Cdk5 is a signal for ubiquitination/degradation, and the degradation of p35 is triggered by glutamate treatment in cultured neurons. p35 is cleaved to p25 by calpain at the time of neuronal cell death, and this limited cleavage is suggested to be the cause of neurodegenerative diseases such as Alzheimer’s disease. Active Cdk5 changes the cellular localization by cleavage of p35 to p25; p35/Cdk5 is associated with membrane or cytoskeletons, but p25/Cdk5 is a soluble protein. Cleavage also increases the life span of p25 and changes the activity or substrate specificity of Cdk5. p25/Cdk5 shows higher phosphorylating activity to tau than p35/Cdk5 in a phosphorylation site-specific manner. Phosphorylation of p35 suppresses cleavage by calpain. Thus, phosphorylation of p35 modulates its proteolytic pattern, stimulates proteasomal degradation and suppresses calpain cleavage. Phosphorylation is age dependent, as p35 is phosphorylated in foetal brains, but unphosphorylated in adult brains. Therefore, foetal phosphorylated p35 is turned over rapidly, whereas adult unphosphorylated p35 has a long life and is easily cleaved to p25 when calpain is activated. p39 is also a short-lived protein and cleaved to the N-terminal truncation form of p29 by calpain. How the metabolism of p39 is regulated, however, is a future problem to be investigated.


  

Author Contacts

Shin-ichi Hisanaga
Department of Biological Sciences, Graduate School of Science
Tokyo Metropolitan University
1-1 Minami-osawa, Hachiohji, Tokyo 192-0397 (Japan)
Tel. +81 426 77 2577, Fax +81 426 77 2559, E-Mail hisanaga-shinichi@c.metro-u.ac.jp

  

Article Information

Received: July 4, 2003
Accepted after revision: September 5, 2003
Number of Print Pages : 9
Number of Figures : 2, Number of Tables : 0, Number of References : 77

  

Publication Details

Neurosignals
Founded 1992 as ‘Biological Signals’ by S.F. Pang (1992–2001) continued as ‘Biological Signals and Receptors’ (1999–2001)

Vol. 12, No. 4-5, Year 2003 (Cover Date: September-October 2003)

Journal Editor: Nancy Y. Ip, Hong Kong
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/journals/nsg


Article / Publication Details

First-Page Preview
Abstract of Review

Received: 7/4/2003
Accepted: 9/5/2003
Published online: 12/18/2003

Number of Print Pages: 9
Number of Figures: 2
Number of Tables: 0

ISSN: 1424-862X (Print)
eISSN: 1424-8638 (Online)

For additional information: http://www.karger.com/NSG


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