Signal transduction by the α6β4 integrin: Distinct β4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes

Department of Pathology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, NY 10016, USA.
The EMBO Journal (Impact Factor: 10.43). 10/1995; 14(18):4470-81. DOI: 10.1093/emboj/19.20.5585
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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.

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Available from: Kishore K Wary, Jan 12, 2015
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    • "In contrast, cross talk has been reported between the canonical Wnt signaling pathway and other signaling pathways [36], [37] and multiple lines of evidence exist that the Wnt pathway is regulated by integrins. For example, beta1 integrin can activate Wnt via the integrin linked kinase (ILK) [38] and the adaptor protein growth factor receptor-bound-2 (Grb-2) has been shown to be recruited by integrin β4 as a result of its interaction with collagen in the extracellular matrix [39] and to enhance β catenin-dependent Wnt signaling [40]. Additional studies are required to establish whether diminished integrin β4-dependent signaling causes down regulation of the canonical Wnt signaling pathway in laminae of laminitic horses, or vice versa, or whether both pathways are down regulated by laminitis-associated changes in other signal pathways. "
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    • "In addition, it has been revealed that in integrin signaling, Shc recruitment to the actin-associated cytoskeleton is important (McGlade et al. 1992, Schlaepfer et al. 1998, Wary et al. 1998). p52 Shc potentiates integrin signaling, and integrin ligation results in the activation of non-receptor tyrosine kinases, such as Src, Fyn, and focal adhesion kinase (FAK), which phosphorylates p52 Shc , leading to Ras activation and entering into the cell cycle (McGlade et al. 1992, Mainiero et al. 1995, Wary et al. 1996, 1998). Besides, the SH3 domain of Fyn interacts with the proline-rich region in the CH1 domain of p52 Shc (Thomas & Bradshaw 1997) and the amino-terminal domain of p52 Shc is shown to mediate the association of this adaptor protein to an actin-rich cellular fraction (Thomas & Bradshaw 1997). "
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    • "In fibroblasts, endothelia and other cell types, FAK activation leads to proliferative signals through the MAPK cascade. An adaptor protein linking FAK to this cascade, Shc, binds only to specific integrin dimers, such as α1β1, α5β1, αvβ3 and α6β4 (Mainiero et al., 1995; Wary, Mainiero, Isakoff, Marcantonio, & Giancotti, 1996). "
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