Mig-6 is a negative regulator of the epidermal growth factor receptor signal.
In contrast to signal generation and transmission, the mechanisms and molecules that negatively regulate receptor tyrosine kinase (RTK) signaling are poorly understood. Here we characterize Mig-6 as a novel negative feedback regulator of the epidermal growth factor receptor (EGFR) and potential tumor suppressor. Mig-6 was identified in a yeast two-hybrid screen with the kinase active domain of the EGFR as bait. Upon EGF stimulation Mig-6 binds to the EGFR involving a highly acidic region between amino acids 985-995. This interaction is kinase activity-dependent, but independent of tyrosine 992. Mig-6 overexpression results in reduced activation of the mitogenactivated protein kinase ERK2 in response to EGF, but not FGF or PDGF, stimulation and in enhanced receptor internalization without affecting the rate of degradation. The induction of Mig-6 mRNA expression in response to EGF, but not FGF, indicates the existence of a negative regulatory feedback loop. Consistent with these findings, a possible role as tumor suppressor is indicated by Mig-6-mediated inhibition of EGFR overexpression-induced transformation of Rati cells.
Hackel
P O
PO
Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Gishizky
M
M
Ullrich
A
A
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000502:physiology; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D019606:Phosphoamino Acids / Q000032:analysis; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques
D002352:Carrier Proteins; C000629925:Errfi1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D019606:Phosphoamino Acids; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases