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

Meierjohann, Svenja; Wende, Elisabeth; Kraiss, Anita; Wellbrock, Claudia; Schartl, Manfred

doi:10.1158/0008-5472.can-05-2667

Cited by 31 publications

(24 citation statements)

References 48 publications

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“…To accomplish this, we used a murine melanocyte cell line which is transgenic for an engineered chimeric EGFR construct (Figure S5A). When these cells are starved by cultivation under reduced serum conditions, they become quiescent, but can be specifically stimulated by EGFR activation, resulting in proliferation and migration [21-23]. EGF treatment led to strong activation of ERK1/2 and AKT in the melanocytes (Figure S5A).…”

Section: Resultsmentioning

confidence: 99%

The MAPK pathway as an apoptosis enhancer in melanoma

et al. 2014

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Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAFV600E–mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAFV600E-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.

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Section: Resultsmentioning

confidence: 99%

The MAPK pathway as an apoptosis enhancer in melanoma

et al. 2014

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“…EGF activates c-Src and induces FAK phosphorylation on a functionally essential residue Y925; both events are critical for EGF-induced cell migration (Fincham and Frame, 1998; Meierjohann et al, 2006). Although EGF stimulates complex formation between EGFR and FAK, no direct interaction of these two proteins has been observed (Sieg et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

SRC-3Δ4 Mediates the Interaction of EGFR with FAK to Promote Cell Migration

et al. 2010

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Summary EGF induces signal transduction between EGFR and FAK, and FAK is required for EGF-induced cell migration. It is unknown, however, what factor mediates the interaction between EGFR and FAK and leads to EGF-induced FAK phosphorylation. Here we identify SRC-3Δ4, a splicing isoform of the SRC-3 oncogene, as a signaling adaptor that links EGFR and FAK and promotes EGF-induced phosphorylations of FAK and c-Src. We identify three PAK1-mediated phosphorylations in SRC-3Δ4 that promote the localization of SRC-3Δ4 to the plasma membrane and mediate the interactions with EGFR and FAK. Importantly, over-expression of SRC-3Δ4 promotes MDA-MB231-induced breast tumor metastasis. Our findings identify phosphorylated SRC-3Δ4 as a missing adaptor between EGFR and its downstream signaling molecule FAK, to coordinately regulate EGF-induced cell migration. Our study also reveals the new concept that a nuclear receptor coactivator can act in the periphery of a cell to directly mediate activation of an enzyme.

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“…Mouse wild-type melanocytes (melan-a WT) [56], lacking endogenous Egfr expression [57,58], were cultured in DMEM, 10% FCS in the presence of cholera toxin (12 nmol/L), and TPA (200 nmol/L). Melan-a WT cells were then stably transfected with the pCS2+-Ola- egfra construct using Fugene transfection reagent (Roche).…”

Section: Methodsmentioning

confidence: 99%

Lineage-specific co-evolution of the Egf receptor/ligand signaling system

et al. 2010

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BackgroundThe epidermal growth factor receptor (Egfr) with its numerous ligands has fundamental roles in development, cell differentiation and physiology. Dysfunction of the receptor-ligand system contributes to many human malignancies. Consistent with such various tasks, the Egfr gene family has expanded during vertebrate evolution as a consequence of several rounds of whole genome duplication. Of particular interest is the effect of the fish-specific whole genome duplication (FSGD) on the ligand-receptor system, as it has supplied this largest group of vertebrates with additional opportunities for sub- and/or neofunctionalization in this signaling system.ResultsWe identified the predicted components of the Egf receptor-ligand signaling system in teleost fishes (medaka, platyfish, stickleback, pufferfishes and zebrafish). We found two duplicated egfr genes, egfra and egfrb, in all available teleost genomes. Surprisingly only one copy for each of the seven Egfr ligands could be identified in most fishes, with zebrafish hbegf being the only exception. Special focus was put on medaka, for which we more closely investigated all Egf receptors and Egfr ligands. The different expression patterns of egfra, egfrb and their ligands in medaka tissues and embryo stages suggest differences in role and function. Preferential co-expression of different subsets of Egfr ligands corroborates the possible subfunctionalization and specialization of the two receptors in adult tissues. Bioinformatic analyses of the ligand-receptor interface between Egfr and its ligands show a very weak evolutionary conservation within this region. Using in vitro analyses of medaka Egfra, we could show that this receptor is only activated by medaka ligands, but not by human EGF. Altogether, our data suggest a lineage-specific Egfr/Egfr ligand co-evolution.ConclusionsOur data indicate that medaka Egfr signaling occurs via its two copies, Egfra and Egfrb, each of them being preferentially coexpressed with different subsets of Egfr ligands. This fish-specific occurrence of Egf receptor specialization offers unique opportunities to study the functions of different Egf receptor-ligand combinations and their biological outputs in vertebrates. Furthermore, our results strongly support the use of homologous ligands in future studies, as sufficient cross-specificity is very unlikely for this ligand/receptor system.

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

Cited by 31 publications

References 48 publications

The MAPK pathway as an apoptosis enhancer in melanoma

The MAPK pathway as an apoptosis enhancer in melanoma

SRC-3Δ4 Mediates the Interaction of EGFR with FAK to Promote Cell Migration

Lineage-specific co-evolution of the Egf receptor/ligand signaling system

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