Spatial Coordination of Kindlin-2 with Talin Head Domain in Interaction with Integrin β Cytoplasmic Tails

Błędzka, Kamila; Liu, Jianmin; Xu, Zhen; Perera, H. Dhanuja; Yadav, Satya Prakash; Białkowska, Katarzyna; Qin, Jun; Qing, Ying; Plow, Edward F.

doi:10.1074/jbc.m111.336743

Cited by 78 publications

(108 citation statements)

References 56 publications

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“…Mice with deficiencies of kindlin-1 and kindlin-3 (Moser et al, 2009a phenotypically recapitulate the Kindler syndrome and LAD-III patients, respectively. Despite their functional importance, the kindlin family members are incapable of unclasping the integrin α/β CT complex (Bledzka et al, 2012) and, consequently, insufficient to induce high integrin activation (Ma et al, 2008;Shi et al, 2007). Because significant interaction between kindlins and TH has not been observed (Bledzka et al, 2012;Yates et al, 2012a), it is mechanistically unclear how the kindlin family supports talin-induced integrin activation.…”

Section: Introductionmentioning

confidence: 99%

“…Despite their functional importance, the kindlin family members are incapable of unclasping the integrin α/β CT complex (Bledzka et al, 2012) and, consequently, insufficient to induce high integrin activation (Ma et al, 2008;Shi et al, 2007). Because significant interaction between kindlins and TH has not been observed (Bledzka et al, 2012;Yates et al, 2012a), it is mechanistically unclear how the kindlin family supports talin-induced integrin activation. Hypothetically, a bridging molecule might exist between kindlin and talin, which could promote integrin activation by facilitating the formation of a multiprotein complex of the key integrin activators.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Gao

Huang

Lai

et al. 2017

Journal of Cell Science

Self Cite

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Wang²,

Thinn³

et al. 2015

Journal of Cell Science

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BSTRACTStudies on the mechanism of integrin inside-out activation have been focused on the role of b-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for a-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the b-integrin membraneproximal region to keep the integrin inactive. The a-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the a-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation.Complete deletion of the a-integrin membrane-distal region diminished talin-and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in a-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the a-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

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“…After binding to a specific ligand, integrins undergo a conformational change (13). Multiple integrins cluster together to trigger intracellular signaling via a concerted interaction between the integrin ␤ subunits and intracellular proteins, such as talin and kindlin (14)(15)(16)(17). The signal is then transmitted to catalytic proteins, such as focal adhesion kinase (FAK), which is a key component of the signal transduction pathways downstream of integrins (18).…”

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confidence: 99%

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

You

et al. 2016

Molecular and Cellular Biology

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c RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I-mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription. Additionally, we show that in kindlin-2 knockout mouse embryonic fibroblasts, overactivation of Ras, Akt, and Src can successfully rescue the defective RNA polymerase I activity induced by the loss of kindlin-2. Finally, through experiments with inhibitors of FAK, Src, and PI3K and rescue experiments in MEFs, we found that the FAK/Src/PI3K/Akt signaling pathway to control rRNA transcription is linear. Collectively, these studies reveal, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth. RNA polymerase I (Pol I) plays a central role in regulating cellular growth and proliferation (1). Eukaryotic cells contain hundreds of ribosomal DNA (rDNA) copies that occupy several different chromosomal locations (2). The production of rRNA can be divided into several steps, i.e., rRNA transcription, modification, and processing, all of which occur in the nucleolus (3, 4). The rate-limiting step is rRNA transcription (1, 5). On sensing of outside stimuli, a preinitiation complex comprised of the transcriptional factors upstream binding factor (UBF), SL1, TBP, Rrn3, and TTF assembles in the promoter region of rDNA. This complex then recruits RNA polymerase I to rDNA loci, and rRNA transcription starts (6-8). In mammalian cells, a single precursor rRNA transcript, 47S rRNA (14.3 kb), is transcribed from rDNA by the RNA polymerase I complex. This large polycistronic transcript encompasses 18S, 5.8S, and 28S rRNAs and includes several spacer regions, which are later processed into distinct rRNA species before assembly into preribosomal subunits (9).The transcriptional activity of Pol I is a fundamental determinant of cell proliferation capacity (3). In rapidly proliferating cells, rRNA production takes more than 50% of all nuclear transcriptional activity. In yeast cells, this percentage can reach more than 80% (10). As such, the tremendous energy consumption demands tight control.At the tissue level, cells attach to the extracellular matrix (ECM) through cell surface receptors termed integrins (11). Integrins are heterodimeric transmembrane receptors comprised of ␣ subunits and ␤ subunits that bind to extracellular ligands, such as laminin, collagen, vitronectin, and fibronectin. Different combinations of the 18 ␣ subunits and 8 ␤ subunits confer specificity on the integrin-ECM interactions (12). After binding ...

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Spatial Coordination of Kindlin-2 with Talin Head Domain in Interaction with Integrin β Cytoplasmic Tails

Cited by 78 publications

References 56 publications

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

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

Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

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