A novel cross-talk between endothelin and ErbB receptors controlling glutamate transporter expression in astrocytes.
The endothelin and epidermal growth factor (EGF) systems are central to the control of reactive brain processes and are thought to partly exert these tasks by endothelin-induced transactivation of the epidermal growth factor receptor (EGFR) Here we show that beyond EGFR transactivation, endothelins prevent the ligand-induced internalization of the EGFR. We unravel that endothelins abrogate internalization of the EGFR by either promoting the formation of "internalization-deficient" EGFR/ErB2-heterodimers or by activating c-Abl kinase, a negative regulator of EGFR internalization. We further provide evidence that this cross-talk is operational in the control of astrocytic glutamate transport. Specifically, we establish that the inhibitory effects exerted by endothelins on basal as well as EGF-induced expression of the major astroglial glutamate transporter subtype, glutamate transporter 1, are a direct consequence of the endothelin-dependent retention of the EGFR at the cell surface. Together our findings unravel a previously unknown cross-talk between endothelin and epidermal growth factor receptors, which may have implications for a variety of pathological conditions.
Institute of Anatomy, University of Leipzig, Medical Faculty, Leipzig, Germany.
Darko
D
Glisic
Claudia
C
Lehmann
Maciej
M
Figiel
Veysel
V
Ödemis
Ricco
R
Lindner
Jürgen
J
Engele
D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D019921:Biotinylation; D015153:Blotting, Western; D001923:Brain Chemistry / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D016232:Endothelins / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D027322:Amino Acid Transport System X-AG; D018076:DNA, Complementary; D016232:Endothelins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D005904:Glial Fibrillary Acidic Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; C483804:Erbb2 protein, rat