Abstract
Integrins require an activation step prior to ligand binding and signaling. How talin and kindlin contribute to these events in non-hematopoietic cells is poorly understood. Here we report that fibroblasts lacking either talin or kindlin failed to activate β1 integrins, adhere to fibronectin (FN) or maintain their integrins in a high affinity conformation induced by Mn(2+). Despite compromised integrin activation and adhesion, Mn(2+) enabled talin- but not kindlin-deficient cells to initiate spreading on FN. This isotropic spreading was induced by the ability of kindlin to directly bind paxillin, which in turn bound focal adhesion kinase (FAK) resulting in FAK activation and the formation of lamellipodia. Our findings show that talin and kindlin cooperatively activate integrins leading to FN binding and adhesion, and that kindlin subsequently assembles an essential signaling node at newly formed adhesion sites in a talin-independent manner.
Highlights
Integrins are heterodimeric transmembrane receptors that mediate cell adhesion to the extracellular matrix (ECM) and to other cells (Hynes, 2002)
Since surface levels of a5 and av integrins remained unchanged between TlnKo and KindKo cells, we were able to establish the specific roles of talin and kindlin for the function of FN-binding integrins under identical conditions
The unambiguity of this finding was unexpected in light of several reports showing that integrin activation and integrinmediated adhesion still occurs in talin-depleted cells, or is inhibited when kindlin-2 is overexpressed (Harburger et al, 2009; Wang et al, 2011; Lawson et al, 2012)
Summary
Integrins are heterodimeric transmembrane receptors that mediate cell adhesion to the extracellular matrix (ECM) and to other cells (Hynes, 2002). The affinity switch proceeds from a bent and clasped low affinity conformation to an extended and unclasped high affinity conformation with an open ligand-binding pocket (Askari et al, 2010; Springer and Dustin, 2012) This change in affinity is believed to be induced through the binding of talin and kindlin to the b integrin cytoplasmic domain (Moser et al, 2009; Shattil et al, 2010) and divalent cations to distinct sites close to the ligandbinding pocket (Gailit and Ruoslahti, 1988; Mould et al, 1995; Xia and Springer, 2014; Mould et al, 2003)
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