A Conserved Lipid-binding Loop in the Kindlin FERM F1 Domain Is Required for Kindlin-mediated αIIbβ3 Integrin Coactivation

Bouaouina, Mohamed; Goult, Benjamin T.; Huet-Calderwood, Clotilde; Bate, Neil; Brahme, Nina N.; Barsukov, Igor; Critchley, David R.; Calderwood, David A.

doi:10.1074/jbc.m111.330845

Cited by 57 publications

(78 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previously reported (Bouaouina et al, 2012a;Goult et al, 2009;), GFP-kindlin-1 and -2 were readily detected in FAs at 24 h after replating (Fig. 1A).…”

Section: Introductionsupporting

confidence: 88%

“…Consistent with this, the F3 subdomain contains a binding site for integrin b-tails, and this binding is required for kindlins to enhance talin-mediated integrin activation Ma et al, 2008;Moser et al, 2008;Ussar et al, 2008). However, subdomain deletion and mutagenesis studies show that kindlin function, and localization to adhesions, also requires the F0, F1 and PH domains, at least in part because of membranebinding sites in these domains (Bouaouina et al, 2012a;Liu et al, 2011;Perera et al, 2011;Xu et al, 2013;Yates et al, 2012). The inability of isolated kindlin subdomains to support integrin activation or signaling has made characterization of the kindlin mechanism of action difficult.…”

Section: Introductionmentioning

confidence: 74%

See 1 more Smart Citation

Differential binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation

Huet-Calderwood

Brahme

Kumar

et al. 2014

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

BSTRACTKindlins are essential FERM-domain-containing focal adhesion (FA) proteins required for proper integrin activation and signaling. Despite the widely accepted importance of each of the three mammalian kindlins in cell adhesion, the molecular basis for their function has yet to be fully elucidated, and the functional differences between isoforms have generally not been examined. Here, we report functional differences between kindlin-2 and -3 (also known as FERMT2 and FERMT3, respectively); GFP-tagged kindlin-2 localizes to FAs whereas kindlin-3 does not, and kindlin-2, but not kindlin-3, can rescue a5b1 integrin activation defects in kindlin-2-knockdown fibroblasts. Using chimeric kindlins, we show that the relatively uncharacterized kindlin-2 F2 subdomain drives FA targeting and integrin activation. We find that the integrin-linked kinase (ILK)-PINCH-parvin complex binds strongly to the kindlin-2 F2 subdomain but poorly to that of kindlin-3. Using a point-mutated kindlin-2, we establish that efficient kindlin-2-mediated integrin activation and FA targeting require binding to the ILK complex. Thus, ILK-complex binding is crucial for normal kindlin-2 function and differential ILK binding contributes to kindlin isoform specificity.

show abstract

“…As previously reported (Bouaouina et al, 2012a;Goult et al, 2009;), GFP-kindlin-1 and -2 were readily detected in FAs at 24 h after replating (Fig. 1A).…”

Section: Introductionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 74%

Differential binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation

Huet-Calderwood

Brahme

Kumar

et al. 2014

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

show abstract

“…The pleckstrin homology (PH) domain inserted in the F 2 subdomian can associate with the plasma membrane and facilitate kindlin recruitment to integrin (Hart et al, 2013;Liu et al, 2011Liu et al, , 2012Yates et al, 2012b). The N-termini of kindlins, including the F 0 and F 1 subdomains, are also involved in supporting integrin activation (Bouaouina et al, 2012;Goult et al, 2009;Ma et al, 2008). Although possible membrane-binding sites have been proposed in the F 0 +F 1 subdomains of kindlins, the exact mechanism by which they support integrin activation remains unclear.…”

Section: Pxn Interacts With Kindlin-1 and Enhances Integrin αIibβ3 Acmentioning

confidence: 99%

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Gao

Huang

Lai

et al. 2017

Journal of Cell Science

View full text Add to dashboard Cite

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.

show abstract

“…It is therefore clear that kindlins are important regulators of integrin activation. Kindlin-1 and -2 localize to integrin-rich FAs where, in addition to controlling integrin activation, they are implicated in regulating downstream integrin signaling and cytoskeletal dynamics (5,8,10,19,20). However, how kindlins modulate signaling and the link to the cytoskeleton has not been clearly resolved.…”

mentioning

confidence: 99%

Kindlin Binds Migfilin Tandem LIM Domains and Regulates Migfilin Focal Adhesion Localization and Recruitment Dynamics

Brahme

Harburger

Kemp-O'Brien

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Migfilin is a focal adhesion protein implicated in control of integrin-mediated cell adhesion, spreading, and migration. Results: Migfilin LIM domains are required for focal adhesion targeting and for binding to kindlin-1 and kindlin-2. Conclusion: Kindlins support migfilin recruitment to focal adhesions and kindlin is important for normal migfilin dynamics in cells. Significance: Migfilin/kindlin interactions are important for regulating subcellular localization.

show abstract

A Conserved Lipid-binding Loop in the Kindlin FERM F1 Domain Is Required for Kindlin-mediated αIIbβ3 Integrin Coactivation

Cited by 57 publications

References 67 publications

Differential binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation

Differential binding to the ILK complex determines kindlin isoform adhesion localization and integrin activation

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Kindlin Binds Migfilin Tandem LIM Domains and Regulates Migfilin Focal Adhesion Localization and Recruitment Dynamics

Contact Info

Product

Resources

About