Misshapen/NIK-related kinase (mink1) is involved in platelet function, hemostasis, and thrombus formation

Abstract

The 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 (MINK12/2) mice, we showed that MINK1 plays an important role in hemostasis and thrombosis via the regulation of platelet functions. In the tail-bleeding assay, MINK12/2 mice exhibited a longer bleeding time thanwild-type(WT) mice (575.2 6 59.7 seconds vs 419.6 6 66.9 seconds). In a model of ferric chloride-induced mesenteric arteriolar thrombosis, vessel occlusion times were twiceaslonginMINK12/2 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 MINK12/2 platelets. Moreover, MINK12/2 platelets demonstrated impaired aggregation and secretion in response to low doses of thrombin and collagen. Furthermore, platelet spreading on fibrinogen was largely hampered in MINK12/2 platelets. The functional differences of MINK12/2 platelets could be attributed to impaired adenosine 59-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. (Blood. 2016;127(7):927-937).