Mutations in the NF2 tumor suppressor gene underlie Neurofibromatosis type 2 (NF2), a familial cancer syndrome featuring the development of central nervous system tumors. The NF2-encoded protein, Merlin, is closely related to the ERM (Ezrin, Radixin and Moesin) proteins, which are thought to facilitate the assembly of membrane:actin cytoskeleton complexes. However, the mechanism whereby Merlin controls cell proliferation is not known. To create an animal model for Nf2-associated tumorigenesis and develop tools for defining the molecular function of Merlin, we generated an Nf2-mutant strain of mice and found that Nf2 mutation predisposes mice to a variety of highly metastatic cancers. This is surprising given the limited spectrum of benign tumors in human NF2 patients and suggests that Nf2 inactivation may play an unrecognized role in cancer development and progression. Our broad objective is to use Nf2-mutant mice and cells to delineate the function of Merlin and its family members in cancer development and progression. We have recently found that a signature of Nf2-deficiency across several types of primary cells is loss of contact-dependent inhibition of proliferation and lack of normal cadherin-mediated cell:cell communication. We discovered that Merlin localizes to cadherin-containing adherens junctions (AJs) in wild-type cells and is required for the establishment of the final actin cytoskeleton associated AJ structure. We also found that silencing of the epidermal growth factor receptor (EGFR) at high cell density, which is known to be mediated by AJ establishment, is defective in the absence of Merlin. The goals of this proposal are to determine whether control of AJ establishment and EGFR silencing is the cellular mechanism whereby Merlin acts as a tumor and metastasis suppressor and to delineate the mechanism of Merlin function in AJ establishment. The results of this study will yield important insight into the mechanism of Merlin function as a tumor suppressor and identify novel targets for therapeutic intervention of NF2.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Chiasson-MacKenzie, Christine; Morris, Zachary S; Liu, Ching-Hui et al. (2018) Merlin/ERM proteins regulate growth factor-induced macropinocytosis and receptor recycling by organizing the plasma membrane:cytoskeleton interface. Genes Dev 32:1201-1214
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

Showing the most recent 10 out of 14 publications