Ligand-independent Dimerization and Activation of the Oncogenic Xmrk Receptor by Two Mutations in the Extracellular Domain

Gómez, Ana; Wellbrock, Claudia; Gutbrod, Heidrun; Dimitrijevic, Nicola; Schartl, Manfred

doi:10.1074/jbc.m006574200

Cited by 46 publications

(41 citation statements)

References 53 publications

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“…Both changes destroy the formation of intramolecular disulfide bonds and allow the formation of intermolecular cysteine bridges between two receptor monomers. (25) This dimer formation mimics the structural effect of ligand binding, which brings the two inactive receptor monomers in contact. Subsequently they become activated and signal from the dimeric state.…”

Section: Tumor Formation In Xiphophorus Fishmentioning

confidence: 91%

Evolution of Xmrk: an oncogene, but also a speciation gene?

Schartl

2008

BioEssays

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Genes that exert their function when they are introduced into a foreign genetic background pose many questions to our current understanding of the forces and mechanisms that promote either the maintenance or divergence of gene functions over evolutionary time. The melanoma inducing Xmrk oncogene of the Southern platyfish (Xiphophorus maculatus) is a stable constituent of the genome of this species. It displays its tumorigenic function, however, almost exclusively only after inter-populational or, even more severely, interspecific hybridization events. The Xiphophorus hybrid melanoma system has gained attention in biomedical research as a genetic model for studying tumor formation. From an evolutionary perspective, a prominent question is: how could this gene persist over millions of years? An attractive hypothesis is that Xmrk, acting as a detrimental gene in a hybrid genome, could be a speciation gene that shields the gene pool of its species from mixing with other closely related sympatric species. In this article, I briefly review our current knowledge of the molecular genetics and biochemical functions of the Xmrk gene and discuss aspects of its evolutionary history and presence with respect to this idea. While Xmrk as a potentially injurious oncogene has clearly survived for millions of years, its role as a speciation gene has to be questioned.

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Section: Tumor Formation In Xiphophorus Fishmentioning

confidence: 91%

Evolution of Xmrk: an oncogene, but also a speciation gene?

Schartl

2008

BioEssays

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“…23 For expression of the proto-oncogene the egfrb cDNA (earlier designated INV) with the CMV enhancer and Tk promoter was used. 21 To generate CMV-Tk::egfrb with the C578S mutation the 1238 bp Sbf1-SgrA1 fragment was replaced by the corresponding fragment from prk5-INV-CS, 22 which contains the C578S mutation. To generate CMV-Tk::egfrb with the G359R mutation the 1238 bp Sbf1-SgrA1 fragment was replaced by the corresponding fragment from prk5-INV-GR, 22 containing the G359R mutation.…”

Section: Expression Plasmidsmentioning

confidence: 99%

“…This dimer formation was also observed for proto-oncogene encoded Egfrb proteins into which the G359R or C578S mutations were introduced. 22 It was thus reasoned that these two mutations induce covalent dimer formation of the Xmrk receptor. This would lead to ligand independent autophosphorylation and consequently constitutive signaling of the receptor as seen in cells expressing the mutant receptors.…”

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confidence: 99%

Activating mutations in the extracellular domain of the melanoma inducing receptor Xmrk are tumorigenic in vivo

Winnemoeller¹,

Wellbrock²,

Schartl³

2005

Intl Journal of Cancer

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Mutated versions or overexpression of receptor tyrosine kinases such as the epidermal growth factor receptor are found frequently in various cancers. In Xiphophorus the formation of hereditary melanoma is caused by the overexpression of the Xmrk oncogene locus. Xmrk is a mutationally altered version of the epidermal growth factor receptor. Two amino acid changes in the extracellular domain of the receptor were shown in vitro to be responsible for a constitutive, ligand-independent activity of Xmrk. To analyze whether these two mutations are indeed responsible for the in vivo oncogenic activity of the receptor, both were independently introduced into the wild-type, non-oncogenic Xiphophorus EGF-receptor and tested in Medaka embryos for their tumorigenic capacity. Both mutations were sufficient to induce tumors after short latency periods and at a comparable frequency as the native Xmrk oncogene. The G359R mutation led to a significantly higher tumor rate than the C578S mutation. Our study shows that subtle point mutations of the EGF-receptor can lead to a highly tumorigenic oncoprotein.

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“…Xmrk-driven melanoma formation in Xiphophorus is a model for receptor tyrosine kinase (RTK)-induced tumorigenesis and a well-established model for the molecular analysis of the successive steps in melanoma development (25,26). Overexpression and mutation of this variant of epidermal growth factor (EGF) receptor (EGFR) induces all molecular events to trigger melanoma formation in this model system (27)(28)(29). The Xmrk-induced melanomas are fast-growing, highly invasive tumors, suggesting that the receptor not only stimulates proliferation but also induces an increased migration of the pigment cells.…”

Section: Introductionmentioning

confidence: 99%

The Oncogenic Epidermal Growth Factor Receptor Variant Xiphophorus Melanoma Receptor Kinase Induces Motility in Melanocytes by Modulation of Focal Adhesions

et al. 2006

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One of the most prominent features of malignant melanoma is the fast generation of metastasizing cells, resulting in the poor prognosis of patients with this tumor type. For this process, cells must gain the ability to migrate. The oncogenic receptor Xmrk (Xiphophorus melanoma receptor kinase) from the Xiphophorus melanoma system is a mutationally activated version of the epidermal growth factor receptor that induces the malignant transformation of pigment cells. Here, we show that the activation of Xmrk leads to a clear increase of pigment cell motility in a fyn-dependent manner. Stimulation of Xmrk induces its interaction with the focal adhesion kinase (FAK) and the interaction of active, receptor-bound fyn with FAK. This results in changes in FAK activity and induces the modulation of stress fibers and focal adhesions. Overexpression of dominant-negative FAK shows that the activity of innate FAK and a receptor-induced focal adhesion turnover are a prerequisite for pigment cell migration. Our findings show that in our system, Xmrk is sufficient for the induction of pigment cell motility and underlines a role of the src family protein tyrosine kinase fyn in melanoma development and progression. (Cancer Res 2006; 66(6): 3145-52)

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Ligand-independent Dimerization and Activation of the Oncogenic Xmrk Receptor by Two Mutations in the Extracellular Domain

Cited by 46 publications

References 53 publications

Evolution of Xmrk: an oncogene, but also a speciation gene?

Evolution of Xmrk: an oncogene, but also a speciation gene?

Activating mutations in the extracellular domain of the melanoma inducing receptor Xmrk are tumorigenic in vivo

The Oncogenic Epidermal Growth Factor Receptor Variant Xiphophorus Melanoma Receptor Kinase Induces Motility in Melanocytes by Modulation of Focal Adhesions

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