title: Hyperactivation of constitutively dimerized oncogenic EGF receptors by autocrine loops.
abstract: The epidermal growth factor (EGF) receptor (EGFR) has a key role in normal embryonic development, adult tissue homeostasis and many pathological processes, in particular tumour formation. Aberrant EGFR activation occurs in many cancer types, and inhibition of this receptor is a promising anti-tumour strategy. Besides overexpression of the wild-type receptor, mutated oncogenic EGFR variants are often associated with malignant transformation. In human non-small-cell lung cancers, kinase mutants of the EGFR are rather common. Human glioblastoma often express the truncated EGFRvIII version as well as other dimerized and permanently activated mutants of the receptor, which are considered as tumour drivers. Similarly, the mutated and dimerized EGFR variant Xiphophorus melanoma receptor kinase (Xmrk) is causative for the development of malignant pigment cell tumours in medaka and Xiphophorus melanoma models. It is generally believed that oncogenic receptors that are active due to dimerizing mutations are ligand independent. Here, we show that different EGFR variants from fish and human efficiently induce autocrine loops by inducing EGFR ligands such as amphiregulin and HB-EGF. Importantly, the pre-dimerized oncogenic EGFR versions Xmrk from Xiphophorus and human EGFR(C600F), though already active in absence of ligands, respond to ligand stimulation with enhanced oncogenic signalling. In summary, our data show that autocrine or paracrine loops are still acting on pre-dimerized oncogenic EGFRs and contribute to their pro-tumorigenic signalling.
authors: Department of Physiological Chemistry I, Biocenter, University of Wuerzburg, Wuerzburg, Germany. juliette.laisney@biozentrum.uni-wuerzburg.de
authors: J A G C
authors: JA
authors: Laisney
authors: T D
authors: TD
authors: Mueller
authors: M
authors: M
authors: Schartl
authors: S
authors: S
authors: Meierjohann
mesh_terms: D000328:Adult; D000818:Animals; D030801:Animals, Genetically Modified; D019898:Autocrine Communication; D003532:Cyprinodontiformes; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008958:Models, Molecular; D055503:Protein Multimerization; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors