The Kindlins: Subcellular localization and expression during murine development

Ussar, Siegfried; Wang, Hao Ven; Linder, Stefan; Fässler, Reinhard; Moser, Markus

doi:10.1016/j.yexcr.2006.06.030

Cited by 221 publications

(286 citation statements)

References 22 publications

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“…The kindlin family members, including kindlin-1, kindlin-2 and kindlin-3, share a high homology with each other but display distinct patterns of tissue-specific expression (Ussar et al, 2006). Kindlin-1 is rich in epithelial cells; a lack of kindlin-1 in humans causes Kindler syndrome, marked with serious skin fragility (Jobard et al, 2003;Siegel et al, 2003).…”

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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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 are evolutionary conserved and consist of three members (11). Hematopoietic cells express Kindlin-3 (11), the deletion of which in mice abrogates integrin activation, resulting in hemorrhages, leukocyte adhesion defects, and osteopetrosis (12)(13)(14).…”

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confidence: 99%

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Moretti

Moser

Lyck

et al. 2013

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

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Activated T cells use very late antigen-4/α4β1 integrin for capture, rolling on, and firm adhesion to endothelial cells, and use leukocyte function-associated antigen-1/αLβ2 integrin for subsequent crawling and extravasation. Inhibition of α4β1 is sufficient to prevent extravasation of activated T cells and is successfully used to combat autoimmune diseases, such as multiple sclerosis. Here we show that effector T cells lacking the integrin activator Kindlin-3 extravasate and induce experimental autoimmune encephalomyelitis in mice immunized with autoantigen. In sharp contrast, adoptively transferred autoreactive T cells from Kindlin-3-deficient mice fail to extravasate into the naïve CNS. Mechanistically, autoreactive Kindlin-3-null T cells extravasate when the CNS is inflamed and the brain microvasculature expresses high levels of integrin ligands. Flow chamber assays under physiological shear conditions confirmed that Kindlin-3-null effector T cells adhere to high concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, albeit less efficiently than WT T cells. Although these arrested T cells polarize and start crawling, only few remain firmly adherent over time. Our data demonstrate that the requirement of Kindlin-3 for effector T cells to induce α4β1 and αLβ2 integrin ligand binding and stabilization of integrin-ligand bonds is critical when integrin ligand levels are low, but of less importance when integrin ligand levels are high.integrin affinity | EAE

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“…1 The three known family members localize to integrin adhesion sites in cells but have different tissue expression patterns. [2][3][4] Kindlin-2 is expressed in embryonic stem cells and almost ubiquitously in tissues, whereas kindlin-1 is restricted to epithelial and kindlin-3 to hematopoietic and endothelial cells. 3,5 The biological relevance of kindlins has been examined through in vitro biochemical, cell-based, and functional assays, as well as in mouse models, and their importance is highlighted through their association with several human genetic disorders.…”

mentioning

confidence: 99%

“…[2][3][4] Kindlin-2 is expressed in embryonic stem cells and almost ubiquitously in tissues, whereas kindlin-1 is restricted to epithelial and kindlin-3 to hematopoietic and endothelial cells. 3,5 The biological relevance of kindlins has been examined through in vitro biochemical, cell-based, and functional assays, as well as in mouse models, and their importance is highlighted through their association with several human genetic disorders. 1 Kindlin-1 defects cause the Kindler syndrome (KS), a form of inherited epidermolysis bullosa that manifests with skin blistering, photosensitivity, and progressive generalized poikiloderma.…”

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confidence: 99%

Kindlin-1 and -2 Have Overlapping Functions in Epithelial Cells

Esser

Heinemann

et al. 2011

The American Journal of Pathology

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Kindlins are a novel family of intracellular adaptor proteins in integrin-containing focal adhesions. Kindlin-1 and -2 are expressed in the skin, but whether and how they cooperate in adult epithelial cells have remained elusive. We uncovered the overlapping roles of kindlin-1 and -2 in maintaining epithelial integrity and show that the phenotype of kindlin-1-deficient cells can be modulated by regulating kindlin-2 gene expression and vice versa. The experimental evidence is provided by use of human keratinocyte cell lines that express both kindlins, just kindlin-1 or kindlin-2, or none of them. Double deficiency of kindlin-1 and -2 had significant negative effects on focal adhesion formation and actin cytoskeleton organization, cell adhesion, survival, directional migration, and activation of ␤ 1 integrin, whereas deficiency of one kindlin only showed variable perturbation of these functions. Cell motility and formation of cell-cell contacts were particularly affected by lack of kindlin-2. These results predict that kindlin-1 and -2 can functionally compensate for each other, at least in part. The high physiologic and pathologic significance of the compensation was emphasized by the discovery of environmental regulation of kindlin-2 expression. UV-B irradiation induced loss of kindlin-2 in keratinocytes. This first example of environmental regulation of kindlin expression has implications for phenotype modulation in Kindler syndrome, a skin disorder caused by kindlin-1 deficiency.

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The Kindlins: Subcellular localization and expression during murine development

Cited by 221 publications

References 22 publications

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells

Kindlin-1 and -2 Have Overlapping Functions in Epithelial Cells

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