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Phosphorylation of the tubulin‐binding protein, stathmin, by Cdk5 and MAP kinases in the brain
Author(s) -
Hayashi Kanehiro,
Pan Yong,
Shu Hongjun,
Ohshima Toshio,
Kansy Janice W.,
White Charles L.,
Tamminga Carol A.,
Sobel André,
Curmi Patrick A.,
Mikoshiba Katsuhiko,
Bibb James A.
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04113.x
Subject(s) - stathmin , cyclin dependent kinase 5 , kinase , biology , phosphorylation , microbiology and biotechnology , protein kinase a , p38 mitogen activated protein kinases , hippocampus , mapk/erk pathway , neuroscience , cyclin dependent kinase 2
Abstract Regulation of cytoskeletal dynamics is essential to neuronal plasticity during development and adulthood. Dysregulation of these mechanisms may contribute to neuropsychiatric and neurodegenerative diseases. The neuronal protein kinase, cyclin‐dependent kinase 5 (Cdk5), is involved in multiple aspects of neuronal function, including regulation of cytoskeleton. A neuroproteomic search identified the tubulin‐binding protein, stathmin, as a novel Cdk5 substrate. Stathmin was phosphorylated by Cdk5 in vitro at Ser25 and Ser38, previously identified as mitogen‐activated protein kinase (MAPK) and p38 MAPKδ sites. Cdk5 predominantly phosphorylated Ser38, while MAPK and p38 MAPKδ predominantly phosphorylated Ser25. Stathmin was phosphorylated at both sites in mouse brain, with higher levels in cortex and striatum. Cdk5 knockout mice exhibited decreased phospho‐Ser38 levels. During development, phospho‐Ser25 and ‐Ser38 levels peaked at post‐natal day 7, followed by reduction in total stathmin. Inhibition of protein phosphatases in striatal slices caused an increase in phospho‐Ser25 and a decrease in total stathmin. Interestingly, the prefrontal cortex of schizophrenic patients had increased phospho‐Ser25 levels. In contrast, total and phospho‐Ser25 stoichiometries were decreased in the hippocampus of Alzheimer's patients. Thus, microtubule regulatory mechanisms involving the phosphorylation of stathmin may contribute to developmental synaptic pruning and structural plasticity, and may be involved in neuropsychiatric and neurodegenerative disorders.