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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113733-08
Application #
8265289
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Woodhouse, Elizabeth
Project Start
2005-08-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$331,162
Indirect Cost
$144,065
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
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
Morris, Zachary S; McClatchey, Andrea I (2009) Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma. Proc Natl Acad Sci U S A 106:9767-72
Larsson, Jonas; Ohishi, Masanobu; Garrison, Brian et al. (2008) Nf2/merlin regulates hematopoietic stem cell behavior by altering microenvironmental architecture. Cell Stem Cell 3:221-7
McClatchey, Andrea I (2007) Neurofibromatosis. Annu Rev Pathol 2:191-216