Phosphorylation of the tubulin-binding protein, stathmin, by Cdk5 and MAP kinases in the brain.
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 MAPKdelta sites. Cdk5 predominantly phosphorylated Ser38, while MAPK and p38 MAPKdelta 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.
Hayashi
Kanehiro
K
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
Pan
Yong
Y
Shu
Hongjun
H
Ohshima
Toshio
T
Kansy
Janice W
JW
White
Charles L
CL
Tamminga
Carol A
CA
Sobel
André
A
Curmi
Patrick A
PA
Mikoshiba
Katsuhiko
K
Bibb
James A
JA
D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D017931:DNA Primers; D013058:Mass Spectrometry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
D017931:DNA Primers; D050777:Stathmin; D014404:Tubulin; C061082:Stmn1 protein, rat; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D020928:Mitogen-Activated Protein Kinases