A Signaling Role for the Uncleaved Form of α6 Integrin in Differentiating Lens Fiber Cells

Abstract

Many alpha integrin subunits are cleaved during their processing to yield heavy and light chains, which remain associated by disulfide bonds. While uncleaved alpha integrin subunits can form functional receptors that sometimes have distinct signaling roles from their better-characterized endoproteolytically cleaved counterparts, their expression at the cell surface and their association with signaling complexes have yet to be determined in vivo. In this study, we demonstrate that, in differentiating lens fiber cells, the uncleaved form of alpha 6 integrin was expressed at the cell surface. This form of alpha 6 integrin coimmunoprecipitated with both the signaling adaptor molecule Shc and its downstream effector Grb2, suggesting that, in lens fiber cells, uncleaved alpha 6 integrin was associated with a Shc-mediated signaling complex. We show that expression of the cleaved form of alpha 6 integrin progressively decreased relative to uncleaved alpha 6 integrin as the state of lens cell differentiation increased, resulting in the predominance of uncleaved alpha 6 integrin in the lens fiber cell zones. Interestingly, we previously have shown that alpha 6 integrin is localized principally along the extensive cell-cell interfaces of these lens fiber cells, in the absence of its extracellular matrix ligand laminin. While we found that the cleaved form of alpha 6 integrin contained both high mannose and complex sugars, the uncleaved form of alpha 6 integrin contained only high mannose sugars. These properties suggest that the uncleaved form of alpha 6 integrin may have a unique role in the embryonic lens. Its high association with Shc and Grb2 in the differentiating cortical fiber cell zone indicates that alpha 6 integrin may provide a cell survival signal in the presence of the apoptotic-like processes that are initiated in this region of the embryonic lens to clear the lens cells of their organelles.

Endoproteolytic Activation of α v Integrin by Proprotein Convertase PC5 Is Required for Vascular Smooth Muscle Cell Adhesion to Vitronectin and Integrin-Dependent Signaling

“…14,15,23 Uncleaved ␣-subunits might have signaling competence, because they are expressed on the cell surface, maintain their RGD-binding properties, 14,15 and coimmunoprecipitate with the integrin-signaling adapter molecules Shr/Gbr2. 28 A central role in mediating integrin signaling is played by the autophosphorylation of FAK at tyrosine 397 on ECM adhesion, which promotes cell motility. 29 It has been shown that adhesion-dependent FAK phosphorylation requires ␣ v cleavage by PCs.…”

Integrin α6β1-laminin interactions regulate early myotome formation in the mouse embryo

“…the closely related ␣3␤1 or ␣7␤1 integrins) are upregulated in the absence of Itga6 expression (see Hynes, 1996). ␣6␤1-laminin interactions have been shown to promote differentiation in some cell types, including skeletal muscle (Sastry et al, 1996) and lens (Walker and Menko, 1999;Walker et al, 2002). However, in these two situations, the differentiation-promoting effect was attributed to the presence of the ␣6A variant.…”

Regulation of cell adhesion and migration in lens development

“…abundant as lens epithelial cells differentiate into lens fibers (Walker et al, 2002a). Although this form is not endoproteolytically processed, it is expressed at the cell surface and associates with signaling molecules such as Shc and Grb2 (Walker et al, 2002a).…”

“…Although this form is not endoproteolytically processed, it is expressed at the cell surface and associates with signaling molecules such as Shc and Grb2 (Walker et al, 2002a).…”