The CaMK4/CREB/IRS-2 Cascade Stimulates Proliferation and Inhibits Apoptosis of β-Cells

Progressive reduction in beta-cell mass is responsible for the development of type 2 diabetes mellitus, and alteration in insulin receptor substrate 2 (IRS-2) abundance plays a critical role in this process. IRS-2 expression is stimulated by the transcription factor cAMP response element-binding protein (CREB) and we recently demonstrated that Ca2+/calmodulin dependent kinase 4 (CaMK4) is upstream of CREB activation in beta-cells. This study investigated whether CaMK4 is also a potential target to increase beta-cell mass through CREB-mediated IRS-2 expression, by quantifying mouse MIN6 beta-cell proliferation and apoptosis following IRS-2 knockdown, CaMKs inhibition and alterations in CaMK4 and CREB expression. Expression of constitutively active CaMK4 (Delta CaMK4) and CREB (CREBDIEDLM) significantly stimulated beta-cell proliferation and survival. In contrast, expression of their corresponding dominant negative forms (Delta(K75E)CaMK4 and CREBM1) and silencing of IRS-2 increased apoptosis and reduced beta-cell division. Moreover, CREBDIEDLM and CREBM1 expression completely abolished the effects of Delta(K75E)CaMK4 and of Delta CaMK4, respectively. Our results indicate that CaMK4 regulates beta-cell proliferation and apoptosis in a CREB-dependent manner and that CaMK4-induced IRS-2 expression is important in these processes.