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Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.
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http://dx.doi.org/10.1038/nm.1921 | DOI Listing |
J Thromb Haemost
July 2024
Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, Wisconsin, USA; Department of Biochemistry, Medical College of Milwaukee, Milwaukee, Wisconsin, USA. Electronic address:
Background: Kindlin-3 in platelets plays an essential role in supporting integrin αβ activation, platelet spreading, aggregation, and clot retraction by binding to the integrin β cytoplasmic tail. However, the mechanism by which kindlin-3 mediates the crosstalk between integrin αβ and myosin in platelets remains unknown.
Objectives: To examine the role of myosin light chain 6 (Myl6) in supporting integrin αβ activation in platelets.
Cell Rep
June 2023
Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan. Electronic address:
Bidirectional control of integrin activation plays crucial roles in cell adhesive behaviors, but how integrins are specifically regulated by inside-out and outside-in signaling has not been fully understood. Here, we report distinct bidirectional regulation of major lymphocyte homing receptors LFA1 and α4β7 in primary T cells. A small increase of Rap1 activation in L-selectin-mediated tether/rolling was boosted by the outside-in signaling from ICAM1-interacting LFA1 through subsecond, simultaneous activation of Rap1 GTPase and talin1, but not kindlin-3, resulting in increased capture and slowing.
View Article and Find Full Text PDFCells
May 2022
Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka 573-1010, Japan.
Integrin LFA1 is a cell adhesion receptor expressed exclusively in leukocytes, and plays crucial roles in lymphocyte trafficking, antigen recognition, and effector functions. Since the discovery that the adhesiveness of LFA1 can be dynamically changed upon stimulation, one challenge has been understanding how integrins are regulated by inside-out signaling coupled with macromolecular conformational changes, as well as ligand bindings that transduce signals from the extracellular domain to the cytoplasm in outside-in signaling. The small GTPase Rap1 and integrin adaptor proteins talin1 and kindlin-3 have been recognized as critical molecules for integrin activation.
View Article and Find Full Text PDFAnticancer Res
March 2022
Versiti Blood Research Institute, Milwaukee, WI, U.S.A.;
Background/aim: Kindlins are essential integrin activators. Kindlin-1 and kindlin-2 are often concomitantly expressed in epithelial tumor cells and participate in regulating tumor malignancy. However, it remains unclear whether kindlin-3, the one expressed in immune cells, also plays a role in regulating tumor malignancy.
View Article and Find Full Text PDFBlood
June 2022
Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA.
Integrins are transmembrane receptors that mediate cell-cell and cell-extracellular matrix adhesion. Although all integrins can undergo activation (affinity change for ligands), the degree of activation is most spectacular for integrins on blood cells. The β2 integrins are exclusively expressed on the surface of all leukocytes including neutrophils, lymphocytes, and monocytes.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!