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PMID: 7556090 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Signal transduction by the alpha 6 beta 4 integrin: distinct beta 4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes.

The EMBO journal ·Vol. 14 ·No. 18 ·1995-09-15 ·Pages 4470-81

Mainiero F, Pepe A, Wary KK, Spinardi L, Mohammadi M, Schlessinger J, Giancotti FG

Abstract

We have examined the mechanism of signal transduction by the hemidesmosomal integrin alpha 6 beta 4, a laminin receptor involved in morphogenesis and tumor progression. Immunoprecipitation and immune complex kinase assays indicated that antibody- or laminin-induced ligation of alpha 6 beta 4 causes tyrosine phosphorylation of the beta 4 subunit in intact cells and that this event is mediated by a protein kinase(s) physically associated with the integrin. Co-immunoprecipitation and GST fusion protein binding experiments showed that the adaptor protein Shc forms a complex with the tyrosine-phosphorylated beta 4 subunit. Shc is then phosphorylated on tyrosine residues and recruits the adaptor Grb2, thereby potentially linking alpha 6 beta 4 to the ras pathway. The beta 4 subunit was found to be phosphorylated at multiple tyrosine residues in vivo, including a tyrosine-based activation motif (TAM) resembling those found in T and B cell receptors. Phenylalanine substitutions at the beta 4 TAM disrupted association of alpha 6 beta 4 with hemidesmosomes, but did not interfere with tyrosine phosphorylation of Shc and recruitment of Grb2. These results indicate that signal transduction by the alpha 6 beta 4 integrin is mediated by an associated tyrosine kinase and that phosphorylation of distinct sites in the beta 4 tail mediates assembly of the hemidesmosomal cytoskeleton and recruitment of Shc/Grb2.

MeSH Terms
Adaptor Proteins, Signal Transducing Amino Acid Sequence Animals Antigens, CD/genetics,metabolism Antigens, Neoplasm/genetics,metabolism Antigens, Surface/metabolism Cell Adhesion/physiology Cell Adhesion Molecules/metabolism Cytoskeleton/metabolism DNA Mutational Analysis Desmosomes/metabolism Fluorescent Antibody Technique GRB2 Adaptor Protein Humans Integrin alpha6beta4 Integrin beta4 Integrins/metabolism Models, Biological Molecular Sequence Data Phosphorylation Protein-Tyrosine Kinases/metabolism Proteins/metabolism Rats Recombinant Proteins/metabolism Sequence Homology, Amino Acid Signal Transduction Transfection src Homology Domains
Chemicals
Adaptor Proteins, Signal Transducing Antigens, CD Antigens, Neoplasm Antigens, Surface Cell Adhesion Molecules GRB2 Adaptor Protein GRB2 protein, human Grb2 protein, rat Integrin alpha6beta4 Integrin beta4 Integrins Proteins Recombinant Proteins kalinin Protein-Tyrosine Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Mainiero F
Department of Pathology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, NY 10016, USA.
Pepe A
Wary K K
Spinardi L
Mohammadi M
Schlessinger J
Giancotti F G
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1995-09-15
Pages
4470-81
Language
English
Region
England
NLM ID
8208664
PMCID
PMC394539
Subset
IM
Grants
NCI NIH HHS · P30-CA16087 · United States
NCI NIH HHS · R01-CA58976 · United States
Corrections
ErratumIn
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External Links
PubMed source PMC Full Text View journal details
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