Constitutive Activation and Specific Signaling of the Xmrk Receptor in Xiphophorus melanoma

Abstract

Receptor tyrosine kinases (RTKs) have been found to play a role in the initiation and progression of different diseases in mammals. Melanoma formation in the fish Xiphophorus is a well-established genetic model in which an RTK is involved in tumorigenesis. The overexpression of the epidermal growth factor receptor–related RTK Xmrk (Xiphophorus melanoma receptor kinase) is the primary step in this hereditary oncogenic condition. In malignant tumors the Xmrk receptor is constitutively activated due to the presence of high levels of receptor molecules containing two activating mutations. These mutations have been localized in the extracellular domain of the receptor, and both lead to the activation of Xmrk through the formation of disulfide-linked dimers. The identification of different intracellular substrates that interact with the activated receptor revealed that proliferative as well as antiapoptotic pathways are involved in the transformation of the pigment cells.