Misshapen/NIK-related kinase (MINK1) is involved in platelet function, hemostasis, and thrombus formation

Abstract

AbstractThe sterile-20 kinase misshapen/Nck-interacting kinase (NIK)–related kinase 1 (MINK1) is involved in many important cellular processes such as growth, cytoskeletal rearrangement, and motility. Here, with MINK1-deficient (MINK1−/−) mice, we showed that MINK1 plays an important role in hemostasis and thrombosis via the regulation of platelet functions. In the tail-bleeding assay, MINK1−/− mice exhibited a longer bleeding time than wild-type (WT) mice (575.2 ± 59.7 seconds vs 419.6 ± 66.9 seconds). In a model of ferric chloride–induced mesenteric arteriolar thrombosis, vessel occlusion times were twice as long in MINK1−/− mice as in WT mice. In an in vitro microfluidic whole-blood perfusion assay, thrombus formation on a collagen matrix under arterial shear conditions was significantly reduced in MINK1−/− platelets. Moreover, MINK1−/− platelets demonstrated impaired aggregation and secretion in response to low doses of thrombin and collagen. Furthermore, platelet spreading on fibrinogen was largely hampered in MINK1−/− platelets. The functional differences of MINK1−/− platelets could be attributed to impaired adenosine 5′-diphosphate secretion. Signaling events associated with MINK1 appeared to involve extracellular signal-regulated kinase, p38, and Akt. Hence, MINK1 may be an important signaling molecule that mediates mitogen-activated protein kinase signaling and participates in platelet activation and thrombus formation.