Role of a serine/threonine kinase, Mst1, in megakaryocyte differentiation

Platelets, which play a central role in thrombosis and hemostasis, develop from megakaryocytes. Signal transduction originated from the megakaryocyte growth and development factor, the MpI ligand, which leads to megakaryocyte differentiation, polyploidization, and maturation, has been gradually char acterized. In this study, we report the inducibility of Mst1, a recently de scribed serine/threonine kinase, by MpI ligand and the effect of its induce d expression on megakaryocyte differentiation. The steady-state level of ms t1 message and Mst1-associated kinase activity increased in response to MpI ligand. Ectopic expression of human mst1 in a mouse megakaryocytic cell li ne resulted in a drastic increase in DNA content per cell. Elevated express ion of megakaryocyte differentiation markers, such as acetylcholine esteras e, PF4, and GPIIb was also observed in hmst1-expressing cells. Activation o f p38 MAPK, a known downstream effector of Mst1, was shown to be required f or polyploidization, but not for enhanced expression of differentiation mar kers. Our study thus designates Mst1 as a MpI ligand-responsive signaling m olecule that promotes induction of lineage-specific cellular programming. J . Cell. Biochem. 76:44-60, 1999. (C) 1999 Wiley-Liss, Inc.