Characterization of the CaMKK?-AMPK signaling complex.

ABSTRACT: The AMP-activated protein kinase (AMPK) is a critical regulator of energy homeostasis, and is a potential target for treatment of metabolic diseases as well as cancer. AMPK can be phosphorylated and activated by the tumor suppressor LKB1 or the Ca(2+)/CaM-dependent protein kinase kinase ? (CaMKK?). We previously identified a physical complex between CaMKK? and AMPK (Anderson, K. A., Ribar, T. J., Lin, F., Noeldner, P. K., Green, M. F., Muehlbauer, M. J., Witters, L. A., Kemp, B. E., and Means, A. R. (2008) Cell Metabolism 7, 377-388). Here we expand our analysis of the CaMKK?-AMPK signaling complex and show that whereas CaMKK? can form a complex with and activate AMPK, CaMKK? cannot. In addition, we show that CaMKK? and AMPK associate through their kinase domains, and CaMKK? must be in an active conformation in order to bind AMPK but not to associate with an alternative substrate, Ca(2+)/Calmodulin-dependent protein kinase IV (CaMKIV). Our results demonstrate that CaMKK? and AMPK form a unique signaling complex. This raises the possibility that the CaMKK?-AMPK complex can be specifically targeted by small molecule drugs to treat disease.

SUBMITTER: Green MF 

PROVIDER: S-EPMC3184326 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature