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J. Biol. Chem., Vol. 275, Issue 27, 20578-20587, July 7, 2000
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From the Department of Cell Biology, The Scripps Research
Institute, La Jolla, California 92037
Microtubule-associated protein 2 (MAP2) and tau,
which is involved in Alzheimer's disease, are major cytoskeletal
proteins in neurons. These proteins are involved in microtubule
assembly and stability. To further characterize MAP2, we took a
strategy of identifying potential MAP2 binding partners. The low
molecular weight MAP2c protein has 11 PXXP motifs that are
conserved across species, and these PXXP motifs could be
potential ligands for Src homology 3 (SH3) domains. We tested for MAP2
interaction with SH3 domain-containing proteins. All neuronal MAP2
isoforms bound specifically to the SH3 domains of c-Src and Grb2 in an
in vitro glutathione S-transferase-SH3
pull-down assay. Interactions between endogenous proteins were
confirmed by co-immunoprecipitation using brain lysate. All three
proteins were also found co-expressed in neuronal cell bodies and
dendrites. Surprisingly, the SH3 domain-binding site was mapped to the
microtubule-binding domain that contains no PXXP motif. Src
bound primarily the soluble, non-microtubule-associated MAP2c in
vitro. This specific MAP2/SH3 domain interaction was inhibited by
phosphorylation of MAP2c by the mitogen-activated protein kinase
extracellular signal-regulated kinase 2 but not by protein
kinase A. This phosphorylation-regulated association of MAP2 with
proteins of intracellular signal transduction pathways suggests a
possible link between cellular signaling and neuronal cytoskeleton,
with MAP2 perhaps acting as a molecular scaffold upon which
cytoskeleton-modifying proteins assemble and dissociate in response to
neuronal activity.
Regulated Association of Microtubule-associated Protein 2 (MAP2) with Src and Grb2: Evidence for MAP2 as a Scaffolding
Protein*
*
This work was supported by National Institutes of Health
Grant MH 50861 (to S. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Department of Cell
Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La
Jolla, CA 92037. Tel.: 858-784-2420; Fax: 858-784-2513; E-mail:
shelley@scripps.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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