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J. Cell Biol.,
Volume 144, Number 6, March 22, 1999 1295-1309
* Department of Cell and Structural Biology, We previously demonstrated contrasting
roles for integrin Department of Pediatrics, and § Department of Biochemistry, University of Illinois,
Urbana, Illinois 61801; and Department of Anatomy and Cell Biology, State University of New York Health Science Center,
Syracuse, New York 13210
subunits and their cytoplasmic domains in controlling cell cycle withdrawal and the onset
of terminal differentiation (Sastry, S., M. Lakonishok,
D. Thomas, J. Muschler, and A.F. Horwitz. 1996. J. Cell
Biol. 133:169-184). Ectopic expression of the integrin 5 or 6A subunit in primary quail myoblasts either decreases or enhances the probability of cell cycle withdrawal, respectively. In this study, we addressed the
mechanisms by which changes in integrin subunit ratios regulate this decision. Ectopic expression of truncated 5 or 6A indicate that the 5 cytoplasmic
domain is permissive for the proliferative pathway
whereas the COOH-terminal 11 amino acids of 6A cytoplasmic domain inhibit proliferation and promote differentiation. The 5 and 6A cytoplasmic domains do
not appear to initiate these signals directly, but instead regulate 
1 signaling. Ectopically expressed IL2R-5 or
IL2R-6A have no detectable effect on the myoblast
phenotype. However, ectopic expression of the 1A integrin subunit or IL2R-1A, autonomously inhibits differentiation and maintains a proliferative state. Perturbing 5 or 6A ratios also significantly affects
activation of 1 integrin signaling pathways. Ectopic 5
expression enhances expression and activation of paxillin as well as mitogen-activated protein (MAP) kinase
with little effect on focal adhesion kinase (FAK). In
contrast, ectopic 6A expression suppresses FAK and MAP kinase activation with a lesser effect on paxillin.
Ectopic expression of wild-type and mutant forms of
FAK, paxillin, and MAP/erk kinase (MEK) confirm
these correlations. These data demonstrate that (a) proliferative signaling (i.e., inhibition of cell cycle withdrawal and the onset of terminal differentiation) occurs
through the 1A subunit and is modulated by the
subunit cytoplasmic domains; (b) perturbing subunit ratios alters paxillin expression and phosphorylation and FAK and MAP kinase activation; (c) quantitative changes in the level of adhesive signaling through
integrins and focal adhesion components regulate the
decision of myoblasts to withdraw from the cell cycle, in
part via MAP kinase.
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