The classical role of AMP-activated protein kinase (AMPK) as an energy status sensor is expanding to include other members of the AMPK family. Recent genetic and cell biological evidence points to a role for MAP/microtubule affinity-regulating kinase 2 (MARK2/EMK/Par1b) in the regulation of metabolic events as well as in the control of CREB-dependent transcription activated by glucose in pancreatic islet beta cells. We have recently developed an in vitro kinase screening platform to identify novel kinase:substrate pairs, the building blocks of signal transduction pathways. Application of this technology led us to identify MARK2 as the kinase that targets a novel glucose-regulated phosphorylation site on Transducer of Regulated CREB Activity 2 (TORC2, referred to as CREB-Regulated Transcriptional Coactivator 2, or CRTC2), a transcriptional coactivator essential for CREB activity in beta cells. We discuss these recent developments and suggest a model whereby members of the AMPK family integrate numerous signals to coordinate energy metabolism and cellular polarity with gene expression to regulate cell function/proliferation.