Cancer develops when cells evade the rules that normally limit their proliferation. Growth factor receptors on the cell surface provide a critical interface between the cell and its environment and are the first intrinsic level of control. Growth factors are often continuously available, necessitating exquisite control of the receptors themselves to ensure that cell division proceeds only when warranted, for example during development, wound healing or normal tissue turnover. The distribution and aggregation of receptors across the plasma membrane is exquisitely choreographed;this, in turn, controls their signaling output and surface abundance via regulated endocytosis. The interface between the membrane and the underlying cortical cytoskeleton plays an active and dynamic role in this choreography. The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, and closely related ERM proteins (Ezrin, Radixin and Moesin), localize to the membrane-cytoskeleton interface and are poised to organize the distribution of, and signaling by, membrane receptors. During the initial funding of this proposal, we discovered that Merlin coordinates the establishment of stable adherens junctions (AJs) between cells with the inhibition of Epidermal Growth Factor Receptor (EGFR) internalization and signaling specifically in contacting cells, suggesting a molecular explanation for how cells achieve the phenomenon of contact-dependent inhibition of proliferation. More recently we have found that, by controlling the membrane distribution of EGFR, Merlin regulates the endocytic pathway taken by EGFR, which, in turn, dictates whether EGFR endocytosis is blocked by cell contact, suggesting a two-step mechanism whereby Merlin controls EGFR. Finally, our most recent studies suggest that Merlin may also control the membrane distribution of ErbB3 via a similar mechanism. Thus Merlin is poised to be a central regulator of the ErbB family of growth factor receptors (EGFR/ErbB1, ErbB2, ErbB3 and ErbB4) that have been implicated in nearly all forms of human cancer. In this application to extend this successful avenue of investigation we propose a multifaceted approach to extending our understanding of the molecular function of Merlin in controlling membrane receptor distribution and signaling. Specifically we plan to delineate the molecular basis of how Merlin controls EGFR membrane distribution and endocytosis and how Merlin stabilizes AJs and blocks EGFR endocytosis upon cell:cell contact. We also plan to determine whether Merlin controls the surface availability of ErbB3 via a similar mechanism.
We will carry out molecular, cellular and in vivo studies to examine the molecular function of the Nf2 tumor suppressor, Merlin. Specifically, we will test the hypothesis that Merlin controls the membrane distribution of and signaling from EGFR in a contact- dependent manner. We will also determine whether Merlin controls the ErbB family member ErbB3 via a similar mechanism. These studies will advance our understanding of the molecular cause of NF2 and of the biology of ErbB receptors that have been widely implicated in human cancer.
|Chiasson-MacKenzie, Christine; Morris, Zachary S; Baca, Quentin et al. (2015) NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. J Cell Biol 211:391-405|
|Shapiro, Irina M; Kolev, Vihren N; Vidal, Christian M et al. (2014) Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med 6:237ra68|
|McClatchey, Andrea I; Yap, Alpha S (2012) Contact inhibition (of proliferation) redux. Curr Opin Cell Biol 24:685-94|
|Blakeley, Jaishri O; Evans, D Gareth; Adler, John et al. (2012) Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2. Am J Med Genet A 158A:24-41|
|Hebert, Alan M; DuBoff, Brian; Casaletto, Jessica B et al. (2012) Merlin/ERM proteins establish cortical asymmetry and centrosome position. Genes Dev 26:2709-23|
|Casaletto, Jessica B; McClatchey, Andrea I (2012) Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer 12:387-400|
|Casaletto, Jessica B; Saotome, Ichiko; Curto, Marcello et al. (2011) Ezrin-mediated apical integrity is required for intestinal homeostasis. Proc Natl Acad Sci U S A 108:11924-9|
|Benhamouche, Samira; Curto, Marcello; Saotome, Ichiko et al. (2010) Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 24:1718-30|
|Gladden, Andrew B; Hebert, Alan M; Schneeberger, Eveline E et al. (2010) The NF2 tumor suppressor, Merlin, regulates epidermal development through the establishment of a junctional polarity complex. Dev Cell 19:727-39|
|McClatchey, Andrea I; Fehon, Richard G (2009) Merlin and the ERM proteins--regulators of receptor distribution and signaling at the cell cortex. Trends Cell Biol 19:198-206|
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