Metabolism: MAD Interactions with Insulin Receptor

RESEARCH HIGHLIGHTS

Nature Reviews Molecular Cell Biology | Published online 21 Jul 2016; doi:10.1038/nrm.2016.97

METABOLISM MAD interactions with insulin receptor Insulin signalling regulates systemic reduced glycogen storage in the kinase (BUBR1; also known as glucose metabolism and its dysreg- liver. Liver-specific knockout mice BUB1B), and this interaction is MCC proteins ulation leads to metabolic disorders, indicated that the loss of p31comet in inhibited by p31comet, leading to are important including diabetes. Choi et al. hepatocytes interfered with insulin MCC inactivation. Similar to the reveal that proteins of the mitotic receptor activation, thereby leading to interactions established during MCC regulators checkpoint complex (MCC), which impaired glycogen synthesis, systemic inactivation, Choi et al. found that of insulin normally function to ensure accurate hyperglycaemia and insulin resistance. p31comet was important for inhibiting signalling chromosome segregation during When analysing the effects of the interaction between BUBR1 and mitosis, have important roles in p31comet loss in mouse hepatocytes insulin receptor-bound MAD2 at the insulin signalling by regulating the in vivo and in human hepatocellular plasma membrane. As BUBR1 has endocytosis of insulin receptors. carcinoma HepG2 cells, the authors been previously shown to interact Choi et al. generated knock- found that insulin receptors localized with adaptor protein 2 (AP2), out mice, in which the negative to intracellular vesicles rather than to which bridges clathrin and cargo for regulator of MCC p31comet (also the plasma membrane. Blocking endocytosis, the authors propose known as MAD2L1BP) was deleted. clathrin-mediated endocytosis that MAD2, together with BUBR1, Unexpectedly, they found that, rescued this aberrant receptor locali- recruits AP2 to the insulin receptors instead of the anticipated increase zation, indicating that p31comet expres- localized at the plasma membrane, in genome instability and thus sion is important to regulate insulin inducing their clathrin-mediated tumorigenesis susceptibility owing receptor internalization through endocytosis; p31comet regulates this to MCC misregulation, these mice endocytosis. process by inhibiting the interaction exhibited neonatal lethality associated To further dissect the role of MCC between MAD2 and BUBR1 to with metabolic defects, most notably proteins in insulin receptor internal- prevent precocious internalization of ization, the authors investigated the non-stimulated insulin receptors. involvement of MAD2 (also known In this study, Choi et al. provide as MAD2L1), a binding partner of new insights into the mechanisms p31comet. Biochemical studies revealed underlying insulin resistance by that MAD2 and the insulin receptor revealing that MCC proteins are directly interact; abolishing this inter- important regulators of insulin action by introducing mutations in signalling. How this novel metabolic the MAD2-interacting motif (MIM) function of mitotic checkpoint prevented insulin receptor endo- regulators is controlled and whether cytosis. Importantly, expression of the mitotic and metabolic roles of MIM-mutant insulin receptors was these proteins are functionally linked able to restore insulin signalling in remain to be elucidated. the p31comet-knockout hepatocytes, Paulina Strzyz

and improved insulin and glucose ORIGINAL ARTICLE Choi, E. et al. Mitotic tolerance of knockout mice. checkpoint regulators control insulin signaling For MCC activation, MAD2 and metabolic homeostasis. Cell http://dx.doi. org/10.1016/j.cell.2016.05.074 (2016) AF Fotografie/Alamy interacts with BUB1-related protein