Functional studies on MST1 and MST2 kinases in mice

Abstract

The Ste-20 family kinase Hippo restricts cell proliferation and promotes apoptosis for proper organ development in $\It{Drosophila}$. In $\It{C. elegans}$, Hippo homolog also regulates longevity. The mammalian Ste20-like protein kinase, MST1 and closely related ortholog MST2, play a role in apoptosis induced by various types of apoptotic stress. MST1 also regulates peripheral naive T cell trafficking and proliferation in mice. However, their functions in mammals are not fully understood. Here, I showed that the MST1-FoxO signaling pathway plays a crucial role in survival, but not apoptosis, of naive T cells. In $\It{Mst1^{-/-}}$ mice, peripheral T cells showed impaired FoxO1/3 activation and decreased FoxO protein levels. Consistently, the FoxO targets, Sod2 and catalase, were significantly down-regulated in $\It{Mst1^{-/-}}$ T cells, thereby resulting in elevated levels of intracellular reactive oxygen species (ROS) and induction of apoptosis. Expression of constitutively active FoxO3a restored $\It{Mst1^{-/-}}$ T cell survival. Crossing Mst1 transgenic mice (Mst1 Tg) with $\It{Mst1^{-/-}}$ mice reduced ROS levels and restored normal numbers of peripheral naive T cells in Mst1 Tg; $\It{Mst1^{-/-}}$ progeny. Interestingly, peripheral T cells from $\It{Mst1^{-/-}}$ mice were hypersensitive to $\gamma$-irradiation and paraquat-induced oxidative stresses, whereas those from Mst1 Tg mice were resistant. These data support the hypothesis that tolerance to increased levels of intracellular ROS provided by the Mst1-FoxOs signaling pathway is crucial for the maintenance of $na\ddot{i}ve$ T cell homeostasis in the periphery. However, $\It{Mst2^{-/-}}$ T cells did not show any defects seen in $\It{Mst1^{-/-}}$ T cells. This implies that MST1 has more major functions than MST2 does in maintaining naive T cell homeostasis. And although MST1 and MST2 also function in apoptotic stress, MEFs from $\It{Mst1^{-/-}}$ and $\It{Mst2^{-/-}}$mice showed normal apoptotic responses t...