A New FYN Signalling Pathway that Activates PAK1 and Inactivates AMPK

Oncogenic RAS mutants activate the RAC/CDC42-dependent kinase PAK1 through a few distinct (and independent) signalling pathways. One is the RAS-PI3 kinase-RAC/CDC42 pathway. A second one is RAS-ETK pathway in which RAS activates ETK gene expression. A third one is RAS-FYN pathway in which RAS activates FYN gene expression. The first pathway can be blocked by CAPE in propolis, which down-regulates RAC. The second pathway can be blocked by the ETK inhibitor AG 879 which interferes with ETK-PAK1 interaction. The last pathway can be blocked by a series of FYN inhibitors such as PP1/PP2 and SU6656.  I have previously described how FYN could activate PAK1 through a tumour suppressor called HT1. HT1 is a direct inhibitor of PAK1, and FYN phosphorylates and inactivates HT1.  

Recently, Claire Bastie’s group at Albert Einstein College of Medicine in NY found another FYN pathway leading to activation of PAK1 (1). They noticed first that FYN-deficient mice have a less fatty (lean) mass than the control normal mice, and in both skeletal muscle and adipose tissue of the former, the higher kinase activity of AMPK, than the latter. Treatment of the control mice with the FYN-inhibitor SU6656 also did lead to a loss of fat and activation of AMPK. Then they found that FYN directly phosphorylates LKB1, the major AMPK activator, at Tyr 261 and 365, for the inactivation, and blocking FYN results in the export of LKB1 into cytoplasm (from nucleus) and activation of AMPK. This indicates that FYN inactivates directly LKB1.  

Since LKB1 is known to inactivate PAK1 and activates AMPK simultaneously, it is now clear that FYN can activate PAK1 by inactivating the two distinct tumour suppressors, LKB1 and HT1. In other words FYN inhibitors would be useful not only for cancer therapy, but also for the treatment of type 2 diabetes and obesity.

Reference: 

1. Yamada E, Pessin JE, Kurland IJ, Schwartz GJ, Bastie CC. Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1. Cell Metab. 2010 11:113-24.