Kindlins: essential regulators of integrin signalling and cell-matrix adhesion

Abstract

Integrin-mediated cell-ECM (extracellular matrix) adhesion is a fundamental process that controls cell behaviour. For correct cell-ECM adhesion, both the ligand-binding affinity and the spatial organization of integrins must be precisely controlled; how integrins are regulated, however, is not completely understood. Kindlins constitute a family of evolutionarily conserved cytoplasmic components of cell-ECM adhesions that bind to beta-integrin cytoplasmic tails directly and cooperate with talin in integrin activation. In addition, kindlins interact with many components of cell-ECM adhesions--such as migfilin and integrin-linked kinase--to promote cytoskeletal reorganization. Loss of kindlins causes severe defects in integrin signalling, cell-ECM adhesion and cytoskeletal organization, resulting in early embryonic lethality (kindlin-2), postnatal lethality (kindlin-3) and Kindler syndrome (kindlin-1). It is therefore clear that kindlins, together with several other integrin-proximal proteins, are essential for integrin signalling and cell-ECM adhesion regulation.

Figure 1

Kindlin domain structure and binding partners. (A) Domain architecture of kindlins and talin. All members of the kindlin protein family show identical domain architecture (top). Arrows indicate the regions of kindlins that interact with β1-integrin and β3-integrin, ILK or migfilin. The interactions with ILK and migfilin are based mainly on the studies of kindlin-2 and UNC-112 (see text). (B) Overlay of the kindlin-2 F3 subdomain model structure (blue) and the talin F3 subdomain structure (green) in complex with the β1-integrin peptide (red) showing a conserved PTB fold. Panel reproduced with permission from Shi et al, 2007. ILK, integrin-linked kinase; PTB, phosphotyrosine binding; UNC-112, uncoordinated protein 112.

Figure 2

Subcellular localization of kindlin-1 and kindlin-2. (A) Human HaCaT keratinocytes stained with monoclonal antibodies that recognize kindlin-1. (B) The cells were dual-stained with rhodamine-phalloidin (red) and anti-kindlin-1 (green). Note that kindlin-1 was concentrated at focal adhesions where actin stress fibres were anchored (arrows). (C) Human HaCaT keratinocytes stained with monoclonal antibodies against kindlin-2. Images kindly provided by G. Owen.

Figure 3

Assembly of kindlin-2-containing cell–ECM adhesions. Model for the assembly of kindlin-2-containing cell–ECM adhesions, which occurs through multiple protein–protein interactions (double arrows). ILK is recruited to cell–ECM adhesions as part of a ternary protein complex (the PINCH–ILK–Parvin complex; Wu, 2004). The interaction between kindlin-2 and ILK (open double arrows) facilitates their localization to cell–ECM adhesions, where they contribute to integrin clustering (filled double arrow) and cytoskeletal organization. ECM, extracellular matrix; ILK, integrin-linked kinase; PINCH, particularly interesting new Cys–His protein.

Figure 4

Clinical manifestations of skin and oral mucosal lesions in Kindler syndrome. (A) A 3-year-old male Kindler syndrome patient with healing ulcers (arrows). (B, C) A 13-year-old male Kindler syndrome patient with acute skin blister (B, arrow) and oral mucosal lesions (C, arrows indicate red, swollen and spontaneously bleeding gingiva). Photographs courtesy of C. Wiebe.

Hannu Larjava

Edward F. Plow

Chuanyue Wu