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An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels
A John Diamonti1, Pamela M Guy, Caryn Ivanof
1Department of Cell Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Abstract:
Despite numerous recent advances in our understanding of the molecular mechanisms underlying receptor tyrosine kinase down-regulation and degradation in response to growth factor binding, relatively little is known about ligand-independent receptor tyrosine kinase degradation mechanisms. In a screen for proteins that might regulate the trafficking or localization of the ErbB3 receptor, we have identified a tripartite or RBCC (RING, B-box, coiled-coil) protein that interacts with the cytoplasmic tail of the receptor in an activation-independent manner. We have named this protein Nrdp1 for neuregulin receptor degradation protein-1. Northern blotting reveals ubiquitous distribution of Nrdp1 in human adult tissues, but message is particularly prominent in heart, brain, and skeletal muscle. Nrdp1 interacts specifically with the neuregulin receptors ErbB3 and ErbB4 and not with epidermal growth factor receptor or ErbB2. When coexpressed in COS7 cells, Nrdp1 mediates the redistribution of ErbB3 from the cell surface to intracellular compartments and induces the suppression of ErbB3 and ErbB4 receptor levels but not epidermal growth factor receptor or ErbB2 levels. A putative dominant-negative form of Nrdp1 potentiates neuregulin-stimulated Erk1/2 activity in transfected MCF7 breast tumor cells. Our observations suggest that Nrdp1 may act to regulate steady-state cell surface neuregulin receptor levels, thereby influencing the efficiency of neuregulin signaling.
Insights
Researchers identified Nrdp1, a protein regulating ErbB3 receptor levels independently of growth factors. Nrdp1 influences neuregulin signaling by controlling receptor trafficking and degradation.
Area of Science:
- Molecular biology
- Cell signaling
- Protein interactions
Background:
- Receptor tyrosine kinase (RTK) degradation is crucial for signal termination.
- Ligand-independent degradation pathways for RTKs remain poorly understood.
- ErbB3 receptor regulation is key in various cellular processes.
Purpose of the Study:
- To identify novel proteins involved in ErbB3 receptor trafficking and degradation.
- To characterize the function of a newly identified RBCC protein, Nrdp1.
- To elucidate the role of Nrdp1 in neuregulin signaling pathways.
Main Methods:
- Protein interaction screening to identify ErbB3-interacting partners.
- Northern blotting to assess Nrdp1 tissue distribution.
- Coexpression studies in COS7 cells to analyze receptor localization and levels.
- Functional assays using dominant-negative Nrdp1 in MCF7 cells.
Main Results:
- Identified Nrdp1, a RING, B-box, coiled-coil (RBCC) protein, interacting with ErbB3.
- Nrdp1 is ubiquitously expressed, with high levels in heart, brain, and skeletal muscle.
- Nrdp1 specifically binds ErbB3 and ErbB4, mediating their internalization and degradation.
- Nrdp1 influences neuregulin-stimulated Erk1/2 activity, suggesting a role in signal modulation.
Conclusions:
- Nrdp1 regulates steady-state cell surface levels of neuregulin receptors (ErbB3/ErbB4).
- Nrdp1 acts as a negative regulator of neuregulin signaling by promoting receptor degradation.
- Nrdp1 represents a novel target for understanding and potentially modulating RTK signaling.