Journal of Biological Chemistry
Volume 285, Issue 48, 26 November 2010, Pages 37650-37662
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Cell Biology
EGF-induced MAPK Signaling Inhibits Hemidesmosome Formation through Phosphorylation of the Integrin β4*

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Migration of keratinocytes requires a regulated and dynamic turnover of hemidesmosomes (HDs). We and others have previously identified three serine residues on the integrin β4 cytoplasmic domain that play a critical role in the regulation of HD disassembly. In this study we show that only two of these residues (Ser-1356 and Ser-1364) are phosphorylated in keratinocytes after stimulation with either PMA or EGF. Furthermore, in direct contrast to previous studies performed in vitro, we found that the PMA- and EGF-stimulated phosphorylation of β4 is not mediated by PKC, but by ERK1/2 and its downstream effector kinase p90RSK1/2. EGF-stimulated phosphorylation of β4 increased keratinocyte migration, and reduced the number of stable HDs. Furthermore, mutation of the two serines in β4 to phospho-mimicking aspartic acid decreased its interaction with the cytoskeletal linker protein plectin, as well as the strength of α6β4-mediated adhesion to laminin-332. During mitotic cell rounding, when the overall cell-substrate area is decreased and the number of HDs is reduced, β4 was only phosphorylated on Ser-1356 by a distinct, yet unidentified, kinase. Collectively, these data demonstrate an important role of β4 phosphorylation on residues Ser-1356 and Ser-1364 in the formation and/or stability of HDs.

Cell Adhesion
Cell Migration
Extracellular Matrix
Integrin
Intermediate Filaments
MAP Kinases (MAPKs)
Protein Phosphorylation
Serine Threonine Protein Kinase

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*

This work was supported by grants from the Dutch Cancer Society and the Netherlands Science Organization (NWO/ALW).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.

1

Present address: Dept. of Anesthesia and Perioperative Care, University of California, San Francisco, CA.