Figure 6. Model for the roles of talin and kindlin during inside-out and outside-in signaling of α5β1 integrin.
Integrin subunits are modelled according to Zhu et al. (2008), with the α5 subunit in green and the β1 subunit in blue showing the bent and clasped low affinity and the extended and unclasped high affinity conformations; the 9EG7 epitope is marked as red dot at the β1 leg and the FN ligand as beige dimers. (A) α5β1 integrin fails to shift from a bent to an extended/unclasped, high affinity state in the absence of talin-1/2 or kindlin-1/2; the bent/clasped conformation brings the EGF-2 domain of the β subunit in close contact with the calf domain of the α5 subunit and prevents exposure of the 9EG7 epitope. (B) In the absence of talin (TlnKo) and presence of Mn2+, kindlin-2 allows adhesion by stabilizing the high affinity conformation of a low number of integrins and the direct binding of paxillin, leading to nucleation of integrins, recruitment of FAK, FAK-dependent signaling and lamellipodia formation. (C) In the absence of kindlins (KindKo), talin stabilizes the high affinity conformation of a low number of integrins but does not enable paxillin recruitment and lamellipodia formation. (D) In normal fibroblasts, binding of kindlin and talin to the β1 tail is associated with the stabilisation of the unclasped α5β1 heterodimer and 9EG7 epitope exposure. (E) Kindlin recruits paxillin and FAK through the kindlin-PH domain and ILK/Pinch/Parvin (IPP; not shown) in a talin-independent manner and induces cell spreading, proliferation and survival. (F) The high affinity conformation of α5β1 integrin is stabilized by linkage of the β1 tail to the actin cytoskeleton through talin (and potentially the IPP complex; not shown). The arrow length indicates integrin conformations existing at equilibrium. EGF, epidermal growth factor; FAK, focal adhesion kinase; FN, fibronectin; ILK, integrin-linked kinase; IPP, integrin-linked kinase-Pinch-Parvin; SFK, src family kinases.