MST1/MST2 Protein Kinases: Regulation and Physiologic Roles

Abstract

The MST1 and MST2 protein kinases comprise the GCK-II subfamily of protein kinases. In addition to their amino-terminal kinase catalytic domain, related to that of the Saccharomyces cerevisiae protein kinase Ste20, their most characteristic feature is the presence near the carboxy terminus of a unique helical structure called a SARAH domain; this segment allows MST1/MST2 to homodimerize and to heterodimerize with the other polypeptides that contain SARAH domains, the noncatalytic polypeptides RASSF1–6 and Sav1/WW45. Early studies emphasized the potent ability of MST1/MST2 to induce apoptosis upon being overexpressed, as well as the conversion of the endogenous MST1/MST2 polypeptides to constitutively active, caspase-cleaved catalytic fragments during apoptosis initiated by any stimulus. Later, the cleaved, constitutively active form of MST1 was identified in nonapoptotic, quiescent adult hepatocytes as well as in cells undergoing terminal differentiation, where its presence is necessary to maintain those cellular states. The physiologic regulation of full length MST1/MST2 is controlled by the availability of its noncatalytic SARAH domain partners. Interaction with Sav1/WW45 recruits MST1/MST2 into a tumor suppressor pathway, wherein it phosphorylates and activates the Sav1-bound protein kinases Lats1/Lats2, potent inhibitors of the Yap1 and TAZ oncogenic transcriptional regulators. A constitutive interaction with the Rap1-GTP binding protein RASSF5B (Nore1B/RAPL) in T cells recruits MST1 (especially) and MST2 as an effector of Rap1’s control of T cell adhesion and migration, a program crucial to immune surveillance and response; loss of function mutation in human MST1 results in profound immunodeficiency. MST1 and MST2 are also regulated by other protein kinases, positively by TAO1 and negatively by Par1, SIK2/3, Akt, and cRaf1. The growing list of candidate MST1/MST2 substrates suggests that the full range of MST1/MST2’s physiologic programs and contributions to pathophysiology remains to be elucidated.

Pharmacological inhibition of Hippo pathway, with the novel kinase inhibitor XMU‐MP‐1, protects the heart against adverse effects during pressure overload

“…3.3 | Mst1/2 inhibition reduces apoptosis and cell death following stress Mst1 and Mst2 exert pro-apoptotic activity in a number of different cell types (Galan & Avruch, 2016). To investigate whether XMU- MP-1 treatment inhibits apoptosis in cardiomyocytes, we treated NRCM with H 2 O 2 (200 μM) for 4 hr to induce oxidative stress and eventually apoptosis, which was assessed by TUNEL assay.…”

“…The two main core kinases of the Hippo pathway, the Mst1 and Mst2, have been implicated in the regulation of cell apoptosis (Galan & Avruch, 2016). Overactivation of Mst1 in cardiomyocytes led to severe cardiomyopathy due to induction of apoptosis (Yamamoto et al, 2003).…”

FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis

“…spheres and human tumors. Apart from the pro-apoptotic nuclear activities, MST1/MST2 function as core Hippo pathway kinases [16,17]. To test if the FGFR4-dependent suppression of MST1/2 activation alters this canonical Hippo tumor suppressor axis, we analyzed YAP S127 phosphorylation and localization in 2D and 3D cultures of MDA-MB-453 shScr and shFGFR4 cells.…”

“…Cytoplasmic MST1/2 comprises the core kinase complex of the mammalian Hippo pathway, which activation ultimately leads to serine phosphorylation-dependent cytoplasmic retention and inactivation of the oncogenic transcriptional regulators, YES-associated protein (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) [15,16]. Upon cell stress and apoptosis, caspase-3 cleavage in turn removes the inhibitory Cterminal domains of MST1/2 to induce transport of the activated N-terminal MST1/2 into the nucleus [17]. Although results from overexpression experiments have shown that nuclear MST1/2 can promote apoptosis [18][19][20][21], and reduced MST1/2 serine/threonine kinase activity has been linked to poor cancer prognosis [22][23][24][25], the functional contribution of endogenous MST1/2 in physiological or pathological apoptotic processes have remained elusive [17].…”

“…Upon cell stress and apoptosis, caspase-3 cleavage in turn removes the inhibitory Cterminal domains of MST1/2 to induce transport of the activated N-terminal MST1/2 into the nucleus [17]. Although results from overexpression experiments have shown that nuclear MST1/2 can promote apoptosis [18][19][20][21], and reduced MST1/2 serine/threonine kinase activity has been linked to poor cancer prognosis [22][23][24][25], the functional contribution of endogenous MST1/2 in physiological or pathological apoptotic processes have remained elusive [17]. Our screening results led us to investigate in more detail the putative direct functional interaction of FGFR4 and MST1/2.…”