MST4

Hippo (MST) MST4 is a serine/threonine kinase of the germinal center kinase III family that regulates cell growth, apoptosis, polarity, migration, and transformation-related signaling programs^[1][2]. Unlike the canonical Hippo kinases MST1 and MST2, which function as core upstream components of the Hippo tumor-suppressor cascade, MST4 primarily acts through distinct signaling modules including ERK-dependent pathways and Golgi-associated regulatory networks, highlighting functional divergence within the MST kinase family^[3][4]. Mechanistically, MST4 localizes to the Golgi apparatus, where interaction with the Golgi matrix protein GM130 contributes to the control of cell polarity and migration. Through modulation of ERK signaling, MST4 promotes cellular proliferation and transformation-related phenotypes in experimental systems^[2][5]. In disease models, elevated MST4 expression has been associated with aggressive behavior in multiple cancers, including prostate cancer and hepatocellular carcinoma, where MST4 enhances proliferation, invasion, epithelial-mesenchymal transition, and metastatic potential^[5][6]. Beyond tumor biology, MST4 also participates in innate immune regulation by phosphorylating TRAF6 and suppressing excessive Toll-like receptor-mediated inflammatory responses, indicating broader functions in tissue homeostasis and host defense^[7]. Compared with related isoforms MST1 and MST2, which are central Hippo pathway regulators, MST4 is more strongly linked to Golgi-associated signaling, ERK activation, and context-dependent regulation of cancer progression and inflammation^[3][7]. Small-molecule MST4 inhibitors have been reported as experimental tools for mechanistic studies and therapeutic target validation in disease models^[8].