The CaMK4/CREB/IRS-2 cascade stimulates proliferation and inhibits apoptosis of β-cells

PLoS One. 2012;7(9):e45711. doi: 10.1371/journal.pone.0045711. Epub 2012 Sep 25.


Progressive reduction in β-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 Ca(2+)/calmodulin dependent kinase 4 (CaMK4) is upstream of CREB activation in β-cells. This study investigated whether CaMK4 is also a potential target to increase β-cell mass through CREB-mediated IRS-2 expression, by quantifying mouse MIN6 β-cell proliferation and apoptosis following IRS-2 knockdown, CaMKs inhibition and alterations in CaMK4 and CREB expression. Expression of constitutively active CaMK4 (ΔCaMK4) and CREB (CREB(DIEDLM)) significantly stimulated β-cell proliferation and survival. In contrast, expression of their corresponding dominant negative forms (Δ(K75E)CaMK4 and CREB(M1)) and silencing of IRS-2 increased apoptosis and reduced β-cell division. Moreover, CREB(DIEDLM) and CREB(M1) expression completely abolished the effects of Δ(K75E)CaMK4 and of ΔCaMK4, respectively. Our results indicate that CaMK4 regulates β-cell proliferation and apoptosis in a CREB-dependent manner and that CaMK4-induced IRS-2 expression is important in these processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism*
  • Cell Proliferation
  • Cell Survival
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Gene Expression Regulation*
  • Glucose / metabolism
  • Humans
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Mice
  • Models, Biological


  • Cyclic AMP Response Element-Binding Protein
  • Insulin Receptor Substrate Proteins
  • CAMK4 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Camk4 protein, mouse
  • Glucose

Grant support

This work was supported by Diabetes UK grants 06/0003387 and 08/0003706 and by a Society for Endocrinology Early Career Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.