The Jak-STAT Signal Transduction Pathway in Melanoma

The Janus-activated kinase (Jak)-signal transducer and activator of transcription (STAT) pathway is thought to play a central role in melanoma cell biology. Membrane-associated Jak proteins can couple with a variety of receptors to transmit signals into the cytoplasm. Immediately downstream, are the STAT family of transcription factors, which can be influenced by a variety of post-translational modifications and localize to the cell nucleus, directly binding DNA. In response to extracellular stimuli or through dysregulated activation of other signaling molecules, STAT proteins are often constitutively phosphorylated or 'activated' in melanoma cells. The balance between the activation of individual STAT proteins influences unique gene expression profiles within melanoma cells. For example, gene expression driven via the STAT1 transcription factor is associated with growth inhibition, resistance to apoptosis and reduced angiogenesis. Conversely, the STAT3 transcription factor mediates a gene expression profile associated with cell growth, antiapoptosis, angiogenesis, metastasis and immune suppression. Altered activity of STAT proteins has been demonstrated in both melanoma cells, and interestingly, in the immune system of patients with melanoma. Recent data suggest that targeting the aberrant activation of this signal transduction pathway could have therapeutic effects via both modulating tumor cell and host immune function. In this chapter, we aim to summarize the role of the Jak-STAT pathway in melanoma, with a focus on the seemingly divergent effect of the STAT1 and STAT3 transcription factors. We will also highlight recent data suggesting that inhibition of signal transduction via the STAT3 pathway may be of interest as a future therapeutic approach for melanoma.