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dc.contributor.authorRabinovitz, Isaac
dc.contributor.authorTsomo, Lobsang
dc.contributor.authorMercurio, Arthur M.
dc.date2022-08-11T08:08:02.000
dc.date.accessioned2022-08-23T15:39:48Z
dc.date.available2022-08-23T15:39:48Z
dc.date.issued2004-05-04
dc.date.submitted2010-11-07
dc.identifier.citationMol Cell Biol. 2004 May;24(10):4351-60.
dc.identifier.issn0270-7306 (Linking)
dc.identifier.pmid15121854
dc.identifier.urihttp://hdl.handle.net/20.500.14038/26258
dc.description.abstractAlthough 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.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=15121854&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1128/MCB.24.10.4351-4360.2004
dc.subjectAmino Acid Sequence
dc.subjectAnimals
dc.subjectBinding Sites
dc.subjectCOS Cells
dc.subjectCell Line
dc.subjectEpidermal Growth Factor
dc.subjectHemidesmosomes
dc.subjectHumans
dc.subjectIntegrin beta4
dc.subjectMutagenesis, Site-Directed
dc.subjectPeptide Mapping
dc.subjectPhosphorylation
dc.subjectProtein Kinase C
dc.subjectProtein Kinase C-alpha
dc.subjectRecombinant Proteins
dc.subjectSerine
dc.subjectTransfection
dc.subjectCancer Biology
dc.subjectNeoplasms
dc.titleProtein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes
dc.typeArticle
dc.source.journaltitleMolecular and cellular biology
dc.source.volume24
dc.source.issue10
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/cancerbiology_pp/172
dc.identifier.contextkey1633397
html.description.abstract<p>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.</p>
dc.identifier.submissionpathcancerbiology_pp/172
dc.contributor.departmentDepartment of Cancer Biology
dc.source.pages4351-60


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