Mechanisms of talin-dependent integrin signaling and crosstalk

Abstract

Cells undergo dynamic remodeling of the cytoskeleton during adhesion and migration on various extracellular matrix (ECM) substrates in response to physiological and pathological cues. The major mediators of such cellular responses are the heterodimeric adhesion receptors, the integrins. Extracellular or intracellular signals emanating from different signaling cascades cause inside-out signaling of integrins via talin, a cystokeletal protein that links integrins to the actin cytoskeleton. Various integrin subfamilies communicate with each other and growth factor receptors under diverse cellular contexts to facilitate or inhibit various integrin-mediated functions. Since talin is an essential mediator of integrin activation, much of the integrin crosstalk would therefore be influenced by talin. However, despite the existence of an extensive body of knowledge on the role of talin in integrin activation and as a stabilizer of ECM-actin linkage, information on its role in regulating inter-integrin communication is limited. This review will focus on the structure of talin, its regulation of integrin activation and discuss its potential role in integrin crosstalk.

The dual structural roles of the membrane distal region of α integrin cytoplasmic tail in integrin inside-out activation

“…Kindlin (which has three isoforms, kindlin-1, -2 and -3) has been found to cooperate with talin during integrin activation through direct binding to the b-integrin CT MD region (Ma et al, 2008;Moser et al, 2008;Harburger et al, 2009;Malinin et al, 2009;Moser et al, 2009b;Svensson et al, 2009;Bledzka et al, 2012). Studies on how talin changes integrin conformation have been focused on the b-integrin TM and CT domains, and have been described in many elegant reviews (Moser et al, 2009a;Shattil et al, 2010;Anthis and Campbell, 2011;Kim et al, 2011b;Calderwood et al, 2013;Das et al, 2014). Recent structural and functional studies suggest that talin-1 binding to the b 3 CT changes the tilt angle of b 3 TM domain in the cell membrane, thus disturbing the a-integrin-b-integrin interfaces at the TM and MP regions (Kalli et al, 2011;Kim et al, 2011a;Kim et al, 2012).…”

Interaction of kindlin-3 and β2-integrins differentially regulates neutrophil recruitment and NET release in mice

“…5,6 Kindlins are recently identified integrin b CT binding proteins, and kindlin-3, one of the 3 kindlin family members, is mainly expressed in hematopoietic cells.…”

“…3,4 Ligand-binding capability of b 2 -integrins on leukocytes is tightly regulated by a process of integrin activation, which is triggered by extracellular agonists and eventually implemented by the integrin a/b cytoplasmic tail (CT) binding proteins. 5,6 Kindlins are recently identified integrin b CT binding proteins, and kindlin-3, one of the 3 kindlin family members, is mainly expressed in hematopoietic cells. [7][8][9] Kindlin-3 mutants in humans are responsible for type III leukocyte adhesion deficiency (LAD-III) with severe bleeding tendency and recurrent infections due to the dysfunction of integrins in both leukocytes and platelets.…”

The role of RIAM in platelets put to a test

“…3 These binding sites in RIAM were suggested to enhance recruitment of talin to membranes and to integrins and thereby increase integrin activation and the consequential cellular responses, including many platelet responses. Indeed, overexpression of RIAM modestly enhances and knockdown of RIAM inhibits activation of the major platelet integrin, aIIbb3, in heterologous cells.…”

“…As currently envisioned, integrin activation depends on the binding of talin via its head domain to the cytoplasmic tail of the integrin b subunit. 3 Talin exists in the cytosol in an autoinhibited state, in which its rod domain occludes the integrin-binding site in its head domain. 7,8 RIAM was envisioned as being involved in activating talin for binding to integrin and in recruiting talin to the membrane, a step needed for appropriate orientation of talin's head for integrin activation.…”