Abstract
The alpha(2) integrin subunit cytoplasmic domain uniquely supported epidermal growth factor (EGF)-stimulated migration on type I collagen. p38 MAP kinase- and phosphatidylinositol 3-kinase-specific inhibitors, but not a MEK-specific inhibitor, eliminated EGF-stimulated and unstimulated alpha(2)-cytoplasmic domain-dependent migration. Following adhesion to collagenous matrices, cells expressing the full-length alpha(2) integrin subunit, but not cells expressing a chimeric alpha(2) integrin subunit in which the alpha(2)-cytoplasmic domain was replaced by the cytoplasmic domain of the alpha(1)-subunit, exhibited sustained and robust phosphorylation of p38 MAP kinase. Expression of dominant negative p38 MAP kinase inhibited alpha(2)-cytoplasmic domain-dependent, EGF-stimulated migration as well as unstimulated migration on collagen. Expression of constitutively active Rac1(Val-12) augmented p38 MAP kinase activation and alpha(2)-cytoplasmic domain-dependent migration. It also rescued the ability of cells expressing the alpha(1)-cytoplasmic domain to activate p38 MAPK and to migrate. These results suggest that the alpha(2) integrin cytoplasmic domain uniquely stimulates the p38 MAP kinase pathway that is required for unstimulated and EGF-stimulated migration on type I collagen.
Highlights
To begin to explore the mechanisms underlying the distinct phenotypes mediated by the two collagen/laminin receptors, we re-expressed either the full-length ␣2 integrin subunit (X2C2) or a chimeric integrin ␣-chain composed of the extracellular and transmembrane domains of the ␣2-subunit fused to the cytoplasmic domain of the ␣1-subunit (X2C1) in a variant subclone of the NMuMG cell line, which lacks endogenous expression of either the ␣11 or the ␣21 integrin
We recently reported that an integrin collagen receptor containing the ␣2 integrin cytoplasmic domain, but not the ␣1 integrin cytoplasmic domain, supported epidermal growth factor (EGF)-stimulated chemotaxis on a matrix of type I collagen [16]
In agreement with these recent observations, NMuMG-3 subclones, lacking endogenous ␣11 and ␣21 integrins, but expressing the full-length ␣2 integrin subunit cDNA construct (X2C2), migrated on type I collagen when stimulated by a chemotactic gradient of EGF (10 ng/ml)
Summary
To begin to explore the mechanisms underlying the distinct phenotypes mediated by the two collagen/laminin receptors, we re-expressed either the full-length ␣2 integrin subunit (X2C2) or a chimeric integrin ␣-chain composed of the extracellular and transmembrane domains of the ␣2-subunit fused to the cytoplasmic domain of the ␣1-subunit (X2C1) in a variant subclone of the NMuMG cell line, which lacks endogenous expression of either the ␣11 or the ␣21 integrin. Expression of dominant negative p38 MAP kinase inhibited ␣2-cytoplasmic domain-dependent, EGF-stimulated migration as well as unstimulated migration on collagen. These results suggest that the ␣2 integrin cytoplasmic domain uniquely stimulates the p38 MAP kinase pathway that is required for unstimulated and EGF-stimulated migration on type I collagen.
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