Fyn kinase function in lipid utilization: a new upstream regulator of AMPK activity?

Abstract

The balance of cellular energy levels in response to changes of nutrient availability, stress stimuli or exercise is a critical step in maintaining tissue and whole body homeostasis. Disruption of this balance is associated with various pathologies, including the metabolic syndrome. Recently, accumulating evidence has demonstrated that the AMP-activated protein kinase (AMPK) plays a central role in sensing changes in energy levels. The regulation of AMPK activity is currently the subject of significant investigation since this enzyme is a potential therapeutic target in both metabolic disorders and tumorigenesis. In this review, we present novel evidence of crosstalk between Fyn, one member of the Src kinase family, and AMPK.

Figure 1

Fyn kinase structure and regulation. Fyn kinase consists of SH1-4 domains. The SH2 domain binds the phosphorylated Y528 in the C-terminus, locking Fyn in an inactive conformation. Y528 is dephosphorylated by phosphatases (PTPs), opening the structure and allowing Y416 in the catalytic SH1 domain to be phosphorylated.

Figure 2

Fyn kinase regulates fatty acid oxidation. Fatty acid oxidation is co-ordinately regulated by the allosteric regulation of carnitine palmitoyl-transferase (CPT-1) activity. CPT-1 activity is inhibited when malonyl-CoA levels are high and activated when malonyl-CoA levels are low. The acetyl-CoA carboxylase (ACC) is the enzyme catalysing the production of malonyl-CoA from acetyl-CoA. ACC is inhibited by AMPK that phosphorylates ACC. AMPK itself is activated when phosphorylated on T172.