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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"In contrast, cross talk has been reported between the canonical Wnt signaling pathway and other signaling pathways ,  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)  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  and to enhance β catenin-dependent Wnt signaling . 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. "
[Show abstract][Hide abstract] ABSTRACT: The digital laminae is a two layer tissue that attaches the distal phalanx to the inner hoof wall, thus suspending the horse's axial skeleton in the hoof capsule. This tissue fails at the epidermal:dermal junction in laminitic horses, causing crippling disease. Basal epithelial cells line the laminar epidermal:dermal junction, undergo physiological change in laminitic horses, and lose versican gene expression. Versican gene expression is purportedly under control of the canonical Wnt signaling pathway and is a trigger for mesenchymal-to-epithelial transition; thus, its repression in laminar epithelial cells of laminitic horses may be associated with suppression of the canonical Wnt signaling pathway and loss of the epithelial cell phenotype. In support of the former contention, we show, using laminae from healthy horses and horses with carbohydrate overload-induced laminitis, quantitative real-time polymerase chain reaction, Western blotting after sodium dodecylsulfate polyacrylamide gel electrophoresis, and immunofluorescent tissue staining, that positive and negative regulatory components of the canonical Wnt signaling pathway are expressed in laminar basal epithelial cells of healthy horses. Furthermore, expression of positive regulators is suppressed and negative regulators elevated in laminae of laminitic compared to healthy horses. We also show that versican gene expression in the epithelial cells correlates positively with that of β-catenin and T-cell Factor 4, consistent with regulation by the canonical Wnt signaling pathway. In addition, gene and protein expression of β-catenin correlates positively with that of integrin β4 and both are strongly suppressed in laminar basal epithelial cells of laminitic horses, which remain E-cadherin(+)/vimentin(-), excluding mesenchymal transition as contributing to loss of the adherens junction and hemidesmosome components. We propose that suppression of the canonical Wnt signaling pathway, and accompanying reduced expression of β catenin and integrin β4 in laminar basal epithelial cells reduces cell:cell and cell:basement membrane attachment, thus, destabilizing the laminar epidermal:dermal junction.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Tyrosine phosphorylation plays a critical role in growth regulation, and its aberrant regulation can be involved in carcinogenesis. The association of Shc (Src homolog and collagen homolog) adaptor protein family members in tyrosine phosphorylation signaling pathway is well recognized. Shc adaptor proteins transmit activated tyrosine phosphorylation signaling that suggest their plausible role in growth regulation including carcinogenesis and metastasis. In parallel, by sharing a similar mechanism of carcinogenesis, the steroids are involved in the early stage of carcinogenesis as well as the regulation of cancer progression and metastatic processes. Recent evidence indicates a cross-talk between tyrosine phosphorylation signaling and steroid hormone action in epithelial cells, including prostate and breast cancer cells. Therefore, the members of Shc proteins may function as mediators between tyrosine phosphorylation and steroid signaling in steroid-regulated cell proliferation and carcinogenesis. In this communication, we discuss the novel roles of Shc proteins, specifically p52(Shc) and p66(Shc), in steroid hormone-regulated cancers and a novel molecular mechanism by which redox signaling induced by p66(Shc) mediates steroid action via a non-genomic pathway. The p66(Shc) protein may serve as an effective biomarker for predicting cancer prognosis as well as a useful target for treatment.
Full-text · Article · Dec 2008 · Endocrine Related Cancer
"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). "
[Show abstract][Hide abstract] ABSTRACT: The development of the mammary gland is spatially regulated by the interaction of the mammary epithelium with the extracellular matrix (ECM). Cells receive cues from the ECM through a family of adhesion receptors called integrins, consisting of alpha- and beta-chain dimers. Integrins assist cells in sensing their appropriate developmental context in response to both hormones and growth factors. Here we argue that cell adhesion to the ECM plays a key role in specific developmental checkpoints, particularly in alveolar survival, morphogenesis and function. Specific ablation of alphabeta1-integrins in the luminal epithelium of the mammary gland shows that this sub-type of receptors is required for proliferation, accurate morphological organisation, as well as milk secretion. Downstream, small Rho GTPases mediate cellular polarisation and differentiation. Current challenges in studying the integration of signals in checkpoints of mammary gland development are discussed.
Full-text · Article · Feb 2007 · The International Journal of Biochemistry & Cell Biology