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    Protein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes

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    Authors
    Rabinovitz, Isaac
    Tsomo, Lobsang
    Mercurio, Arthur M.
    UMass Chan Affiliations
    Department of Cancer Biology
    Document Type
    Journal Article
    Publication Date
    2004-05-04
    Keywords
    Amino Acid Sequence
    Animals
    Binding Sites
    COS Cells
    Cell Line
    Epidermal Growth Factor
    Hemidesmosomes
    Humans
    Integrin beta4
    Mutagenesis, Site-Directed
    Peptide Mapping
    Phosphorylation
    Protein Kinase C
    Protein Kinase C-alpha
    Recombinant Proteins
    Serine
    Transfection
    Cancer Biology
    Neoplasms
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    Link to Full Text
    http://dx.doi.org/10.1128/MCB.24.10.4351-4360.2004
    Abstract
    Although the regulation of hemidesmosome dynamics during processes such as epithelial migration, wound healing, and carcinoma invasion is important, the mechanisms involved are poorly understood. The integrin alpha 6 beta 4 is an essential component of the hemidesmosome and a target of such regulation. Epidermal growth factor (EGF) can induce hemidesmosome disassembly by a mechanism that involves serine phosphorylation of the beta 4 integrin subunit. Using a combination of biochemical and mutational analyses, we demonstrate that EGF induces the phosphorylation of three specific serine residues (S(1356), S(1360), and S(1364)) located within the connecting segment of the beta 4 subunit and that phosphorylation on these residues accounts for the bulk of beta 4 phosphorylation stimulated by EGF. Importantly, phosphorylation of these serines is critical for the ability of EGF to disrupt hemidesmosomes. Using COS-7 cells, which assemble hemidesmosomes type II upon exogenous expression of the alpha 6 beta 4 integrin, we observed that expression of a beta 4 construct containing Ser-->Ala mutations of S(1356), S(1360), and S(1364) reduced the ability of EGF to disrupt hemidesmosomes and that this effect appears to involve cooperation among these phosphorylation sites. Moreover, expression of Ser-->Asp mutants that mimic constitutive phosphorylation reduced hemidesmosome formation. Protein kinase C-alpha (PKC-alpha) is the kinase responsible for phosphorylating at least two of these serines, based on in vitro kinase assays, peptide mapping, and mutational analysis. Together, these results highlight the importance of serine phosphorylation in regulating type II hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of beta 4, and argue for a key role for PKC-alpha in regulating these structures.
    Source
    Mol Cell Biol. 2004 May;24(10):4351-60.
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/26258
    PubMed ID
    15121854
    Related Resources
    Link to Article in PubMed
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    UMass Chan Faculty and Researcher Publications

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