Tyrosine phosphorylation of the beta 4 integrin cytoplasmic domain mediates Shc signaling to extracellular signal-regulated kinase and antagonizes formation of hemidesmosomes.

Details

Serval ID
serval:BIB_D2207DF5D463
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Tyrosine phosphorylation of the beta 4 integrin cytoplasmic domain mediates Shc signaling to extracellular signal-regulated kinase and antagonizes formation of hemidesmosomes.
Journal
Journal of Biological Chemistry
Author(s)
Dans M., Gagnoux-Palacios L., Blaikie P., Klein S., Mariotti A., Giancotti F.G.
ISSN
0021-9258
Publication state
Published
Issued date
01/2001
Peer-reviewed
Oui
Volume
276
Number
2
Pages
1494-1502
Language
english
Abstract
Ligation of the alpha(6)beta(4) integrin induces tyrosine phosphorylation of the beta(4) cytoplasmic domain, followed by recruitment of the adaptor protein Shc and activation of mitogen-activated protein kinase cascades. We have used Far Western analysis and phosphopeptide competition assays to map the sites in the cytoplasmic domain of beta(4) that are required for interaction with Shc. Our results indicate that, upon phosphorylation, Tyr(1440), or secondarily Tyr(1422), interacts with the SH2 domain of Shc, whereas Tyr(1526), or secondarily Tyr(1642), interacts with its phosphotyrosine binding (PTB) domain. An inactivating mutation in the PTB domain of Shc, but not one in its SH2 domain, suppresses the activation of Shc by alpha(6)beta(4). In addition, mutation of beta(4) Tyr(1526), which binds to the PTB domain of Shc, but not of Tyr(1422) and Tyr(1440), which interact with its SH2 domain, abolishes the activation of ERK by alpha(6)beta(4). Phenylalanine substitution of the beta(4) tyrosines able to interact with the SH2 or PTB domain of Shc does not affect incorporation of alpha(6)beta(4) in the hemidesmosomes of 804G cells. Exposure to the tyrosine phosphatase inhibitor orthovanadate increases tyrosine phosphorylation of beta4 and disrupts the hemidesmosomes of 804G cells expressing recombinant wild type beta(4). This treatment, however, exerts a decreasing degree of inhibition on the hemidesmosomes of cells expressing versions of beta(4) containing phenylalanine substitutions at Tyr(1422) and Tyr(1440), at Tyr(1526) and Tyr(1642), or at all four tyrosine phosphorylation sites. These results suggest that beta(4) Tyr(1526) interacts in a phosphorylation-dependent manner with the PTB domain of Shc. This event is required for subsequent tyrosine phosphorylation of Shc and signaling to ERK but not formation of hemidesmosomes.
Keywords
Amino Acid Substitution, Antigens, CD/metabolism, Antigens, CD/physiology, Antigens, Surface/physiology, Binding Sites, Cell Line, Cytoplasm/physiology, Desmosomes/drug effects, Desmosomes/physiology, Enzyme Inhibitors/pharmacology, Humans, Integrin alpha6, Integrin alpha6beta4, Integrin beta4, Integrins/physiology, Phenylalanine, Phosphopeptides/chemistry, Phosphorylation, Phosphotyrosine/metabolism, Recombinant Proteins/metabolism, Signal Transduction/physiology, Transfection, Tyrosine, Vanadates/pharmacology, src Homology Domains
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 8:34
Last modification date
20/08/2019 15:52
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