title: Regulation of cell adhesion and migration by Kindlin-3 cleavage by calpain.
abstract: Integrin activation on hematopoietic cells is essential for platelet aggregation, leukocyte adhesion, and transmigration through endothelium and extracellular matrix into inflamed tissues. To migrate through matrix, leukocyte integrin adhesion complexes undergo dynamic changes. Here we show that Kindlin-3, a main activator and binding partner of integrins in hematopoietic cells, can be cleaved by calpain in an activation-dependent manner. This calpain-mediated cleavage occurs in platelets and leukocytes as well as in endothelial cells. We determined the calpain I cleavage site in Kindlin-3 at tyrosine 373 in the N-terminal part of Kindlin-3 pleckstrin homology domain. Expression of the calpain-resistant Y373N mutant of Kindlin-3 promotes stronger cell adhesion to extracellular matrix under flow as well as to activated endothelium. In contrast, Y373N mutation in Kindlin-3 hinders cell migration. Mechanistically, calpain-resistant Y373N mutant of Kindlin-3 exhibited an activation-independent association with β integrin cytoplasm domain. Thus, cleavage of Kindlin-3 by calpain controls the dynamics of integrin-Kindlin-3 interaction and as a result, integrin-dependent adhesion and migration of hematopoietic cells. This represents a novel mechanism regulating reversibility of integrin adhesion complexes in leukocytes, which, in turn, is critical for their successful transmigration through the extracellular matrix.
authors.affiliation: Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Nikolay L
authors.initials: NL
authors.lastname: Malinin
authors.forename: Julia
authors.initials: J
authors.lastname: Meller
authors.forename: Yi
authors.initials: Y
authors.lastname: Ma
authors.forename: Xiaoxia Z
authors.initials: XZ
authors.lastname: West
authors.forename: Kamila
authors.initials: K
authors.lastname: Bledzka
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Podrez
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
mesh_terms: D019943:Amino Acid Substitution; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis
chemical_list: C477322:FERMT3 protein, human; D016023:Integrins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D002154:Calpain