The “beta cell Hippo pathway” under physiological and pathological conditions

Abstract

Diabetes mellitus is a complex metabolic disorder characterized by insulin deficiency, typically resulting from an inadequate dysfunctional beta-cell mass. One of the major hallmarks for the tremendous decline in the functional beta-cell mass is beta-cell apoptosis, namely the loss of beta-cell through apoptotic cell death. The Hippo signaling pathway is a prominent regulator of organ size and tissue homeostasis which is indispensable for the regulation of both beta-cell dysfunction and apoptosis. Our lab identified that the core component of the Hippo pathway, mammalian sterile 20-like 1 (MST1) kinase, is chronically activated in human and rodent beta-cells under multiple experimental models of diabetes as well as in pathological specimens. Genetic inhibition of MST1 restored beta-cell viability and function. Consequently, MST1 inhibition could be a promising approach for beta-cell protective therapy in diabetes. In the first part of my thesis, I showed that neratinib, a well-known irreversible pan- HER/EGFR tyrosine kinase inhibitor, could potently inhibit MST1, its downstream signaling, and subsequent apoptosis in beta-cells under diabetogenic conditions and also restored functional beta-cell mass in models of both autoimmune associated type 1 diabetes and obesity-associated type 2 diabetes. In the second part, I investigated the downstream target of MST1, namely the large tumor suppressor homolog 1/2 (LATS1/2) kinase in the regulation of stress-responsive signaling pathways and beta-cell apoptosis. Endogenous LATS1/2 activity was highly upregulated in beta cells/islets under diabetic conditions. LATS2 deficiency in both isolated rodents and human islets was sufficient to rescue beta-cells from apoptosis. Moreover, in vivo data revealed the potential beta-cell protective phenotype of beta-cell specific LATS2-KO mice during high fat/ high sugar-induced beta-cell decompensation and failure as well as in a model of severe beta-cell destruction. Mechanistically, I determined the mutual crosstalk between Hippo-LATS2, mTORC1, and the intracellular recycling system of autophagy. LATS2 worked upstream of mTORC1 in mediating beta-cell apoptosis under diabetic conditions and LATS2-induced mTORC1 activation mediated autophagic impairment and exacerbated beta-cell apoptosis. My data also show that the macroautophagy machinery regulates LATS2’s protein turnover in beta cells at the basal level. Altogether, my work highlights the existence of bidirectional crosstalk between autophagy and Hippo-LATS2 in pancreatic beta cells. Hence, targeting the Hippo components MST1 and LATS2 might be a potent therapeutic strategy for beta-cell protection in diabetes.