Binding of α-melanocyte-stimulating hormone to its G-protein-coupled receptor on B-lymphocytes activates the Jak/STAT pathway

alpha-Melanocyte-stimulating hormone (alpha-MSH) is a 13-amino-acid peptide with a variety of physiological effects, including the stimulation of melanocyte proliferation and melanogenesis, temperature control, control of prolactin release and the modulation of cytokine action in the immune system. There are five known subtypes of G-protein-coupled receptors, which bind with different affinities to alpha-MSH. This paper provides evidence that Ba/F3 pro-B-lymphocyte cells express the gene for the melanocortin 5 (MC5) receptor and specifically bind alpha-MSH. Western-blot analysis reveals that alpha-MSH binding stimulates Janus kinase 2 (JAK2) and signal transducers and activators of transcription (STAT1) tyrosine phosphorylation in both Ba/F3 cells and human cultured IM-9 lymphocytes. alpha-MSH is further revealed to activate JAK2 in mouse L-cells stably expressing the human MC5 receptor. Finally, alpha-MSH binding is shown to result in an enhancement of cellular proliferation. These findings identify a new protein tyrosine kinase pathway in the action of alpha-MSH, and suggest that alpha-MSH plays an important role in B-lymphocyte function via the activation of the same intracellular phosphorylation pathway used by cytokines and growth factors.