The Met receptor tyrosine kinase regulates a complex array of cellular behaviors collectively known as "invasive growth." While essential for normal development and wound repair, this program is frequently co-opted by tumors to promote their own growth, motility, and invasion. Met is overexpressed in a variety of human tumors, and this aberrant expression correlates with poor patient prognosis. Previous studies indicate that Met receptor levels are governed in part by cbl-mediated ubiquitination and degradation, and uncoupling of Met from cbl-mediated ubiquitination promotes its transforming activity. Here we describe a novel mechanism for Met degradation. We find that the Met receptor interacts with the transmembrane protein LRIG1 independent of hepatocyte growth factor (HGF) stimulation and that LRIG1 destabilizes the Met receptor in a cbl-independent manner. Overexpression of LRIG1 destabilizes endogenous Met receptor in breast cancer cells and impairs their ability to respond to HGF. LRIG1 knockdown increases Met receptor half-life, indicating that it plays an essential role in Met degradation. Finally, LRIG1 opposes Met synergy with the ErbB2/Her2 receptor tyrosine kinase in driving cellular invasion. We conclude that LRIG1 is a novel suppressor of Met function, serving to regulate cellular receptor levels by promoting Met degradation in a ligand-and cbl-independent manner.
Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1 (NRG1) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1 signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1 binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1 treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.The ErbB family of receptor tyrosine kinases includes ErbB1/ epidermal growth factor (EGF) 3 receptor, ErbB2/Her2/Neu, ErbB3, and ErbB4. The EGF-like growth factor family of ligands binds the extracellular domain of the ErbB receptors leading to the formation of both homo-and heterodimers. Receptor dimer formation is followed by autophosphorylation of receptor intracellular domains, recruitment of intracellular signaling proteins, and the initiation of a number of signaling cascades that regulate cellular growth, motility, and survival. ErbB receptors play critical roles both in development and tissue maintenance (1), and their overexpression and aberrant activation have been implicated in the genesis and progression of a variety of human tumors (2).While in general receptor heterodimerization is thought to diversify ErbB signaling (1), heterodimerization with ErbB2 is required for ErbB3 signaling in response to the neuregulin-1 (NRG1) growth factor. No soluble growth factor ligand has been identified that binds to ErbB2, but it is the preferred dimerization partner of the other ErbB family members. Thus, it is thought that its function is to heterodimerize with the other ErbB family members to enhance signaling. ErbB3 is a binding receptor for NRG1 but lacks intrinsic kinase activity (3) and is not capable of signaling on its own. The ErbB2-ErbB3 heterodimer efficiently activates the Ras/Erk pathway, and the C-terminal domain of ErbB3 contains six binding sites for the p85 subunit of PI3K that very efficiently couple the activated receptor ...
Background: The institutions which comprise the Clinical and Translational Science Award consortium and the National Center for Advancing Translational Sciences continue to explore and develop community engaged research strategies and to study the role of community academic partnerships in advancing the science of community engagement. Objectives: To explore Clinical and Translational Science institutions (CTSA) in relation to an Institute of Medicine recommendation that community engagement occur in all stages of translational research and be defined and evaluated consistently. Methods: A sequential multi-methods study starting with an online pilot survey followed by survey respondents and site informant interviews. A revised survey was sent to the community engagement and evaluation leads at each CTSA institution, requesting a single institutional response about definitions, indicators and metrics of community engagement and community-engaged research. Results: A plurality of CTSA institutions selected the definition of community engagement from the Principles of Community Engagement. While claiming unique institutional priorities create barriers to developing shared metrics, responses indicate an overall lack of attention to the development and deployment of metrics to assess community engagement in and contributions to research. Conclusions: Although definitions of community engagement differ among CTSAs, there appears more similarities than differences in the indicators and measures tracked and reported on across all definitions, perhaps due to commonalities among program infrastructures and goals. Metrics will likely need to be specific to translational research stages. Assessment of community engagement within translational science will require increased institutional commitment.
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