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MBC in Press, published online ahead of print November 12, 2008
Mol. Biol. Cell 10.1091/mbc.E08-06-0646

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Submitted on June 25, 2008
Revised on October 27, 2008
Accepted on October 30, 2008

Phosphorylation of a Novel Site on the {beta}4 Integrin at the Trailing Edge of Migrating Cells Promotes Hemidesmosome Disassembly

Emily C. Germain, Tanya M. Santos, and Isaac Rabinovitz

Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115

Monitoring Editor: Richard O. Hynes

Hemidesmosomes (HDs) are multiprotein structures that anchor epithelial cells to the basement membrane. HD components include the {alpha}6{beta}4 integrin, plectin, and BPAGs (bullous pemphigoid antigens). HD disassembly in keratinocytes is necessary for cells to migrate, and can be induced by EGF through {beta}4 integrin phosphorylation. We have identified a novel phosphorylation site on the {beta}4 integrin: S1424. Preventing phosphorylation by mutating S->A1424 results in increased incorporation of {beta}4 into HDs and resistance to EGF-induced disassembly. In contrast, mutating S->D1424 (mimicking phosphorylation) partially mobilizes {beta}4 from HDs and potentiates the disassembly effects of other phosphorylation sites. In contrast to previously described sites that are phosphorylated upon growth factor stimulation, S1424 already exhibits high constitutive phosphorylation suggesting additional functions. Constitutive phosphorylation of S1424 is distinctively enriched at the trailing edge of migrating keratinocytes where HDs are disassembled. Although most of this S1424-phosphorylated {beta}4 is found dissociated from HDs, a substantial amount can be associated with HDs near the cell margins, colocalizing with plectin but always excluding BPAGs, suggesting that phospho-S1424 might be a mechanism to dissociate {beta}4 from BPAGs. S1424 phosphorylation is PKC dependent. These data suggest an important role for S1424 in the gradual disassembly of HDs induced by cell retraction.

Address correspondence to: Isaac Rabinovitz (irabinov{at}bidmc.harvard.edu)






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