Interferon alpha (IFNalpha) is widely used in treatment of malignant melanoma 
patients. This cytokine acts on cells by engaging Type I IFN receptor consisting 
of two subunits, (IFNAR1 and IFNAR2) followed by activation of Janus kinases 
(Jak). Levels of IFNAR1 (regulated via degradation mediated by the betaTrcp E3 
ubiquitin ligase) and IFNalpha signaling were reduced in 1205Lu melanoma cell 
line that harbors activated BRAF and exhibits high levels of betaTrcp ubiquitin 
ligase. Expression of stabilized IFNAR1 in melanoma cells decreased their 
tumorigenicity. Furthermore, RNAi-mediated BRAF knockdown and pharmacologic 
inhibition of either Raf or MEK1 decreased levels of betaTrcp and stabilized 
IFNAR1. However, despite causing stabilization of IFNAR1, Raf inhibitor BAY 
43-9006 interfered with cellular responses to IFNalpha most likely due to its 
ability to directly inhibit Jak activity. We discuss the implications of this 
result for combination therapy with BAY 43-9006 and IFNalpha in melanoma 
patients.