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Mig-6 is a negative regulator of the epidermal growth factor receptor signal
P O Hackel1, M Gishizky, A Ullrich
1Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Abstract:
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.
Insights
Mig-6 acts as a negative regulator for epidermal growth factor receptor (EGFR) signaling. This novel feedback mechanism involves Mig-6 binding to EGFR, reducing downstream signaling, and potentially suppressing tumors.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- Mechanisms negatively regulating receptor tyrosine kinase (RTK) signaling are poorly understood.
- Identifying negative regulators is crucial for understanding RTK signaling pathways and developing targeted therapies.
Purpose of the Study:
- To characterize Mig-6 as a novel negative feedback regulator of epidermal growth factor receptor (EGFR) signaling.
- To investigate the potential role of Mig-6 as a tumor suppressor.
Main Methods:
- Yeast two-hybrid screening using the EGFR kinase active domain.
- Assessing Mig-6 binding to EGFR upon epidermal growth factor (EGF) stimulation.
- Evaluating the impact of Mig-6 overexpression on ERK2 activation and receptor internalization.
- Analyzing Mig-6 mRNA expression in response to growth factor stimulation.
- Assessing Mig-6-mediated inhibition of EGFR-induced cell transformation.
Main Results:
- Mig-6 was identified as an EGFR-interacting protein, binding to a specific acidic region (amino acids 985-995) in a kinase activity-dependent manner.
- Mig-6 overexpression reduced EGF-stimulated ERK2 activation and enhanced EGFR internalization, but not degradation.
- EGF stimulation induced Mig-6 mRNA expression, suggesting a negative feedback loop.
- Mig-6 inhibited EGFR overexpression-induced transformation of Rati cells, indicating a tumor suppressor role.
Conclusions:
- Mig-6 is a novel negative feedback regulator of EGFR signaling.
- Mig-6 enhances EGFR internalization and dampens downstream signaling, forming a regulatory loop.
- Mig-6 exhibits tumor suppressor activity by inhibiting EGFR-driven transformation.