Inside-out signaling versus Outside-in signaling[Edit]
Different signaling pathways can initiate integrin activation via:
a) Inside-out signaling
Signals received by other receptors foster the binding of talin and kindlin to cytoplasmic end of the integrin β subunit [1], at sites of actin polymerization. Substantial information on signaling pathway leading activation is available for integrin αIIbβ3 [2].Talin binds to integrin β-tail via F3 phospho-tyrosine binding (PTB) domain [3], a unique interaction with the membrane proximal (MP) region of the integrin (NPxY motif). This permits competition between conserved lysine on talin and an aspartic acid on integrin α essential for α/β salt bridge disruption and sufficient for integrin activation [4, 5]. Addition interactions through the basic patches in the FERM subdomain F2 helps to orient the β-subunit to promote spatial separation of the cytoplasmic domains [6, 7].
Kindlin is also an essential co-activator of integrin [8, 9] and binds to a membrane distal NxxY motif on β-integrin via its FERM F3 subdomain [10]. A preceding threonine patch on integrins β1 and β3 that gets phosphorylated [10, 11] and a tryptophan on kindlin F3 are also required for binding. However, kindlins are not known to activate integrins on their own but may render integrin-specific effects (reviewed in [12]).
The mechanism of crosstalk between integrin, talin and kindlin are not well established (reviewed in [13]). However, substantial data on the order of their binding is available. Latest Findings Talin is recruited directly to FAs from the cytosol suggesting that it does not bind to free diffusing integrins outside FAs [14] and also requires vinculin and F-actin for its activation [15]. Hence it is believed that only F-actin anchored talin at FAs bind free diffusing integrin promoting its activation [14]. Talin can directly connect to actin while kindlin links through adaptors such as migfilin, filamin, FAK, VASP and α-actinin (reviewed in [12]).
b) Outside-in signaling
Ligand binding to external domain causes conformational changes that increase ligand affinity, modify protein-interaction sites in the cytoplasmic domains and thence the resulting signals.
Besides conformational changes that extend integrin dimers ([16], reviewed in [17, 18]), multivalent ligand binding leads to clustering of integrins, which in turn activates Src family of kinases (SFKs) by autophosphorylation [19]. SFKs phosphorylate tyrosines of the integrin cytoplasmic domain (NPxY motifs) [20, 21] and other proteins [22, 23] leading to
a) control of ligand binding strength
b) alteration of binding with signaling molecules (kinases, GTPases and adaptors) [24], that constitute dynamic adhesion structures such as focal adhesions and podosomes (reviewed in [25, 26]).
Besides conformational changes that extend integrin dimers ([16], reviewed in [17, 18]), multivalent ligand binding leads to clustering of integrins, which in turn activates Src family of kinases (SFKs) by autophosphorylation [19]. SFKs phosphorylate tyrosines of the integrin cytoplasmic domain (NPxY motifs) [20, 21] and other proteins [22, 23] leading to
a) control of ligand binding strength
b) alteration of binding with signaling molecules (kinases, GTPases and adaptors) [24], that constitute dynamic adhesion structures such as focal adhesions and podosomes (reviewed in [25, 26]).