ACTIVATION OF THE XMRK PROTOONCOGENE OF XIPHOPHORUS BY OVEREXPRESSIONAND MUTATIONAL ALTERATIONS

Xmrk is a receptor tyrosine kinase closely related to the human EGF re ceptor, In the teleost fish Xiphophorus two versions of the Xmrk gene exist, an oncogene (ONC) and a proto-oncogene (INV), While ONC-Xmrk is the melanoma-inducing gene, INV-Xmrk appears not to be involved in tr ansformation of pigment cells, To elucidate the mechanism that convert s the proto-oncogene into a transforming oncogene a comparative analys is of the structure, expression and function of both versions of the g ene was performed, In contrast to ONC-Xmrk which is expressed at high levels in melanoma cells, the protooncogene INV-Xmrk is ubiquitously e xpressed at very low levels indicating overexpression as one possible reason for tumorigenicity by ONC-Xmrk. As sequence comparison of the p roto-oncogene and the oncogene revealed a number of amino acid changes , a possible effect of these mutations on the activation of the ONC-Xm rk receptor was determined, A constitutive activation of the oncogenic receptor was found and ectopic expression of INV-Xmrk after microinje ction into medakafish embryos did not lead to the high tumour rate in transgenic fish as observed for the oncogene. Our data therefore sugge st that overexpression of the receptor alone is not sufficient for mel anoma induction, but that in addition activating mutations in ONC-Xmrk are responsible for its full tumorigenic potential.