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

Brahme, Nina N.; Harburger, David S.; Kemp-O'Brien, Karl; Stewart, Rachel; Raghavan, Srikala; Parsons, Maddy; Calderwood, David A.

doi:10.1074/jbc.m113.483016

Cited by 26 publications

(37 citation statements)

References 41 publications

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“…As kindlin-2 binds ILK more efficiently than kindlin-3 does, we aimed to test whether knocking down endogenous kindlin-2 in NIH3T3 fibroblasts (Brahme et al, 2013) would permit GFPkindlin-3 localization in FAs. Our knockdown fibroblasts exhibited only ,15% residual kindlin-2 (Fig.…”

Section: Ilk Binding Aids Kindlin-2 Fa Targetingmentioning

confidence: 99%

“…Although all three kindlins play key roles in integrin activation, isoform-specific differences in activation have also been described . We therefore compared kindlin-2 and -3 rescue of a5b1 activation in kindlin-2-knockdown NIH3T3 fibroblasts (Brahme et al, 2013). The ability of integrins to bind soluble ligand provides a widely used functional readout of integrin activation (Bouaouina et al, 2012b;Calderwood, 2004b).…”

Section: Ilk Binding Is Important For Kindlin-2-mediated B1 Integrin mentioning

confidence: 99%

“…TRC library-based lentiviral scramble (catalog no. SHC002) and kindlin-2 short hairpin (sh)RNA (TRCN000019185) plasmids were purchased from Sigma and lentivirus was produced as previously described (Bandyopadhyay et al, 2012;Brahme et al, 2013).…”

Section: Constructsmentioning

confidence: 99%

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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

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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.

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Section: Ilk Binding Aids Kindlin-2 Fa Targetingmentioning

confidence: 99%

Section: Ilk Binding Is Important For Kindlin-2-mediated B1 Integrin mentioning

confidence: 99%

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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

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“…In addition to β-integrins, multiple kindlin binding proteins (KBPs) have been identified, such as migfilin for kindlin-1 and kindlin-2 (Brahme et al, 2013;Tu et al, 2003), Src and F-actin for kindlin-2 (Bledzka et al, 2016;Liu et al, 2015;Qu et al, 2014), and RACK1 for kindlin-3 (Feng et al, 2012). It has been shown that these KBPs are involved in regulating integrin-mediated cell adhesion and spreading (outside-in signaling), but not integrin activation (insideout signaling).…”

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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“…The protein product of FERMT1 is KIND1, a key intracellular component of focal adhesions, which tightly connects cells to the extracellular matrix. Focal adhesions contain clusters of transmembrane integrin adhesion receptors and intracellular proteins that link integrins to the actin cytoskeleton and to signaling pathways (Brahme et al 2013). Therefore, it is possible that molecular defects in the basement membrane could weaken the attachment of junctional epithelium to tooth surfaces, which could increase the susceptibility of a patient to periodontal disease (Wiebe and Larjava 1998).…”

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confidence: 99%

New Perspectives on Amelotin and Amelogenesis

Bartlett¹,

Simmer

2015

J Dent Res

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

Cited by 26 publications

References 41 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

New Perspectives on Amelotin and Amelogenesis

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