MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes

nature medicine VOLUME 20 | NUMBER 4 | APRIL 2014 385 Pancreatic beta cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to the reduced beta cell mass in type 2 diabetes (T2D)1–4. In both cases, the mechanisms of beta cell death are complex and as yet not fully defined. Thus, multiple triggering factors have been identified; these factors initiate a variety of signaling cascades that affect the expression of apoptotic genes, leading to subsequent beta cell failure. In T1D, autoimmune destruction of insulin-producing beta cells and critically diminished beta cell mass are hallmarks of the disease2. Beta cell destruction occurs through immune-mediated processes; mononuclear cell infiltration in the pancreatic islets and interaction between antigen-presenting cells and T cells lead to high local concentrations of inflammatory cytokines, chemokines, reactive oxygen species and other apoptotic triggers (for example, the perforin and Fas–Fas ligand systems)2. In T2D, beta cell dysfunction and reduced beta cell mass are the ultimate events leading to the development of clinically overt disease in insulin-resistant individuals. Beta cell destruction is caused by multiple stimuli including glucotoxicity, lipotoxicity, proinflammatory cytokines, endoplasmic reticulum stress and oxidative stress5. Unfortunately, although it has been demonstrated that even a small amount of preserved endogenous insulin secretion has great benefits in terms of clinical outcome6, none of the currently widely used antidiabetic agents target the maintenance of endogenous beta cell mass. Beta cells are highly sensitive to apoptotic damages induced by multiple stressors such as inflammatory and oxidative assault, owing at least in part to their low expression of cytoprotective enzymes7. The initial trigger of beta cell death still remains unclear; it follows an orchestra of events, which makes the initiation of beta cell death complex and its blockade difficult to successfully achieve in vivo. Therefore, the identification of a common key regulator of beta cell apoptosis would offer a new therapeutic target for the treatment of diabetes. The identification of the genes that regulate apoptosis has laid the foundation for the discovery of new drug targets. MST1 (also known as STK4 and KRS2) is a ubiquitously expressed serine-threonine kinase that is part of the Hippo signaling pathway and involved in multiple cellular processes such as morphogenesis, proliferation, stress response and apoptosis8,9. MST1 is a target and activator of caspases, serving to amplify the apoptotic signaling pathway10,11. Thr183 in subdomain VIII of MST1 has been defined as a primary site for the phosphoactivation and the autophosphorylation of MST1 and is essential for kinase activation. Both phosphorylation and caspase-mediated cleavage are required for full activation of MST1 during apoptosis. MST1 promotes cell death through regulation of multiple downstream targets such as LATS1 and LATS2, histone H2B and members of the FOXO family, as well as through induction of stress kinase c-Jun-N-terminal kinase (JNK) and activation of caspase-3 (refs. 9,12,13). Genetic mutations and/or metabolic disturbances can alter protein networks and thereby disrupt downstream signaling pathways that are essential for beta cell survival and function. The transcription factor pancreatic duodenal homeobox-1 (PDX1, previously called IPF1, IDX1, STF1 or IUF1)14,15 is a key mediator of beta cell development and function16. In humans, mutations in the PDX1 gene can predispose individuals to develop maturity onset diabetes of the young, type 4 (MODY 4)17, suggesting a critical role for PDX1 in