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Mol. Cell. Biol., Jan 1995, 186-197, Vol 15, No. 1
Copyright © 1995, American Society for Microbiology
Association of p62, a multifunctional SH2- and SH3-domain-binding protein, with src family tyrosine kinases, Grb2, and phospholipase C gamma-1
S Richard, D Yu, KJ Blumer, D Hausladen, MW Olszowy, PA Connelly and AS Shaw
Center for Immunology, Washington University School of Medicine, St Louis, Missouri 63110.
src family tyrosine kinases contain two noncatalytic domains termed src
homology 3 (SH3) and SH2 domains. Although several other signal
transduction molecules also contain tandemly occurring SH3 and SH2 domains,
the function of these closely spaced domains is not well understood. To
identify the role of the SH3 domains of src family tyrosine kinases, we
sought to identify proteins that interacted with this domain. By using the
yeast two-hybrid system, we identified p62, a tyrosine-phosphorylated
protein that associates with p21ras GTPase- activating protein, as a src
family kinase SH3-domain-binding protein. Reconstitution of complexes
containing p62 and the src family kinase p59fyn in HeLa cells demonstrated
that complex formation resulted in tyrosine phosphorylation of p62 and was
mediated by both the SH3 and SH2 domains of p59fyn. The phosphorylation of
p62 by p59fyn required an intact SH3 domain, demonstrating that one
function of the src family kinase SH3 domains is to bind and present
certain substrates to the kinase. As p62 contains at least five
SH3-domain-binding motifs and multiple tyrosine phosphorylation sites, p62
may interact with other signalling molecules via SH3 and SH2 domain
interactions. Here we show that the SH3 and/or SH2 domains of the
signalling proteins Grb2 and phospholipase C gamma-1 can interact with p62
both in vitro and in vivo. Thus, we propose that one function of the
tandemly occurring SH3 and SH2 domains of src family kinases is to bind
p62, a multifunctional SH3 and SH2 domain adapter protein, linking src
family kinases to downstream effector and regulatory molecules.
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