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J. Biol. Chem., Vol. 276, Issue 19, 16374-16378, May 11, 2001
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From the Departments of Molecular Pharmacology and
Phosphoinositide (PI) 3-kinases are
required for the acute regulation of the cytoskeleton by growth
factors. We have shown previously that in the MTLn3 rat adenocarcinoma
cells line, the p85/p110
N-terminal Domains of the Class IA Phosphoinositide
3-Kinase Regulatory Subunit Play a Role in Cytoskeletal but Not
Mitogenic Signaling*
§, and Anatomy and Structural Biology, Albert Einstein College
of Medicine, Bronx, New York
PI 3-kinase is required for epidermal
growth factor (EGF)-stimulated lamellipod extension and
formation of new actin barbed ends at the leading edge of the cell. We
have now examined the role of the p85 regulatory subunit in greater
detail. Microinjection of recombinant p85 into MTLn3 cells blocked
both EGF-stimulated mitogenic signaling and lamellipod extension. In
contrast, a truncated p85(1-333), which lacks the SH2 and iSH2
domains and does not bind p110, had no effect on EGF-stimulated
mitogenesis but still blocked EGF-stimulated lamellipod extension.
Additional deletional analysis showed that the SH3 domain was not
required for inhibition of lamellipod extension, as a construct
containing only the proline-rich and breakpoint cluster region (BCR)
homology domains was sufficient for inhibition. Although the BCR domain
of p85 binds Rac, the effects of the p85 constructs were not because of
a general inhibition of Rac signaling, because sorbitol-induced JNK
activation in MTLn3 cells was not inhibited. These data show that the
proline-rich and BCR homology domains of p85 are involved in the
coupling of p85/p110 PI 3-kinases to regulation of the actin
cytoskeleton. These data provide evidence of a distinct cellular
function for the N-terminal domains of p85.
*
This work was funded in part by a grant from the American
Cancer Society and National Institutes of Health Grant RO1
GM556982 (to J. M. B) and by National Institutes of Health Training
Grant 5T32 GM07260 (to K. M. 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.
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