The kindlin family: functions, signaling properties and implications for human disease

Rognoni, Emanuel; Ruppert, Raphael; Fässler, Reinhard

doi:10.1242/jcs.161190

Cited by 193 publications

(192 citation statements)

References 137 publications

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“…The talin head alone can shift the integrin conformation towards an active state (Box 1), but there is increasing evidence that forces generated by actin polymerisation and myosin contraction are involved in inducing or stabilising the extended-open conformation (Comrie et al, 2015;Nordenfelt et al, 2016). This additional mechanism fits well with the discovery of other IAPs that cooperate with talin to activate integrins, such as kindlins, although the mechanism is still unclear and kindlins also cluster integrins (Moser et al, 2009;Calderwood et al, 2013;Ye et al, 2013;Rognoni et al, 2016;Georgiadou et al, 2017). Additional IAPs enhancing talinmediated activation are RIAM (Han et al, 2006;Yang et al, 2014), zasp (also known as LDB3) (Bouaouina et al, 2012) and vinculin (Lee et al, 2013), whereas other IAPs compete with talin and reduce activation, including ICAP1 (also known as ITGB1BP1) (Bouvard et al, 2003), filamin A (Kiema et al, 2006) and moesin (Vitorino et al, 2015).…”

Section: Talin In Integrin Activationmentioning

confidence: 70%

Talin – the master of integrin adhesions

Klapholz

Brown

2017

Journal of Cell Science

249

222

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Talin has emerged as the key cytoplasmic protein that mediates integrin adhesion to the extracellular matrix. In this Review, we draw on experiments performed in mammalian cells in culture and Drosophila to present evidence that talin is the most important component of integrin adhesion complexes. We describe how the properties of this adaptor protein enable it to orchestrate integrin adhesions. Talin forms the core of integrin adhesion complexes by linking integrins directly to actin, increasing the affinity of integrin for ligands (integrin activation) and recruiting numerous proteins. It regulates the strength of integrin adhesion, senses matrix rigidity, increases focal adhesion size in response to force and serves as a platform for the building of the adhesion structure. Finally, the mechano-sensitive structure of talin provides a paradigm for how proteins transduce mechanical signals to chemical signals.

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Section: Talin In Integrin Activationmentioning

confidence: 70%

Talin – the master of integrin adhesions

Klapholz

Brown

2017

Journal of Cell Science

249

222

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“…Meanwhile, the F 3 subdomain of TH also recognizes the membrane-proximal residues of the integrin β CTs and is thus capable of unclasping the integrin α/β CT complex and triggering integrin activation (Wegener et al, 2007); in addition, other subdomains in TH are functionally supportive by facilitating membrane attachment (Goult et al, 2010). Besides talin, multiple lines of evidence, from model cells to genetically modified mice to human patients, have clearly shown that kindlins are also essentially involved in supporting integrin activation (Larjava et al, 2008;Plow et al, 2009;Rognoni et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Gao

Huang

Lai

et al. 2017

Journal of Cell Science

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Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F 0 subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbβ3 activation. Both kindlin and talin were required for paxillin to enhance integrin activation. Interestingly, a direct interaction between paxillin and the talin head domain was also detectable. Mechanistically, paxillin, together with kindlin, was able to promote the binding of the talin head domain to integrin, suggesting that paxillin complexes with kindlin and talin to strengthen integrin activation. Specifically, we observed that crosstalk between kindlin-3 and the paxillin family in mouse platelets was involved in supporting integrin αIIbβ3 activation and in vivo platelet thrombus formation. Taken together, our findings uncover a novel mechanism by which kindlin supports integrin αIIbβ3 activation, which might be beneficial for developing safer anti-thrombotic therapies.

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“…Kindlin2 is ubiquitously expressed, and loss of kindlin2 in mice leads to peri-implantation lethality (11). Kindlins are also involved in tumorigenesis and metastasis (19). The kindlin-associated diseases are due, at least in part, to impaired integrin activation, focal adhesion (FA) formation, and cell spreading (10,12).…”

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confidence: 99%

Structural basis of kindlin-mediated integrin recognition and activation

Deng

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

140

182

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Kindlins and talins are integrin-binding proteins that are critically involved in integrin activation, an essential process for many fundamental cellular activities including cell-matrix adhesion, migration, and proliferation. As FERM-domain-containing proteins, talins and kindlins, respectively, bind different regions of β-integrin cytoplasmic tails. However, compared with the extensively studied talin, little is known about how kindlins specifically interact with integrins and synergistically enhance their activation by talins. Here, we determined crystal structures of kindlin2 in the apo-form and the β1-and β3-integrin bound forms. The apo-structure shows an overall architecture distinct from talins. The complex structures reveal a unique integrin recognition mode of kindlins, which combines two binding motifs to provide specificity that is essential for integrin activation and signaling. Strikingly, our structures uncover an unexpected dimer formation of kindlins. Interrupting dimer formation impairs kindlin-mediated integrin activation. Collectively, the structural, biochemical, and cellular results provide mechanistic explanations that account for the effects of kindlins on integrin activation as well as for how kindlin mutations found in patients with Kindler syndrome and leukocyte-adhesion deficiency may impact integrin-mediated processes.I ntegrins, composed of α-and β-subunits, are the major receptors mediating the cell-extracellular matrix (ECM) adhesion (1-3). By connecting specific ECM proteins and diverse cytoskeletal regulators, integrins mediate bidirectional transmembrane signaling (4, 5). Stable integrin-ECM interaction and subsequent signaling require integrin activation, which was reported to be mediated by talin, a 4.1-protein/ezrin/radixin/moesin (FERM) domain-containing protein (6). Recently, kindlins, another family of FERM-containing proteins, were found to play crucial roles in integrin activation and signaling (7-12).The kindlin family consists of three members in vertebrates, kindlin1/2/3, each containing a FERM domain and a PH domain (Fig. 1A) (13). Compared with the typical FERM domain that consists of three lobes (F1, F2, and F3), kindlin-FERM contains an additional N-terminal F0 lobe. In kindlins, the F1 and F2 lobes are split by a largely unstructured insertion and the PH domain, respectively (Fig. 1A). Kindlins, although sharing high sequence similarity (SI Appendix, Fig. S1), show distinct tissue distributions and nonredundant functions. Kindlin1 is expressed mainly in epithelia, and nonfunctional kindlin1 mutations lead to Kindler syndrome, a congenital skin disease (14-16). Expression of kindlin3 is restricted to the hematopoietic system, and mutations in kindlin3 were found to associate with leukocyte-adhesion deficiency type III (LADIII) (17, 18). Kindlin2 is ubiquitously expressed, and loss of kindlin2 in mice leads to peri-implantation lethality (11). Kindlins are also involved in tumorigenesis and metastasis (19). The kindlin-associated diseases are due, at least in part...

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The kindlin family: functions, signaling properties and implications for human disease

Cited by 193 publications

References 137 publications

Talin – the master of integrin adhesions

Talin – the master of integrin adhesions

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Structural basis of kindlin-mediated integrin recognition and activation

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