Functional Relationship between Merlin and the ERM Proteins

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Functional Relationship between Merlin and the ERM Proteins

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dc.contributor.advisor McClatchey, Andrea Irene
dc.contributor.author Hebert, Alan
dc.date.accessioned 2012-11-15T17:16:23Z
dash.embargo.terms 2013-10-05 en_US
dash.embargo.terms 2013-10-05
dc.date.issued 2012-11-15
dc.date.submitted 2012
dc.identifier.other http://dissertations.umi.com/gsas.harvard:10567 en
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:9909639
dc.description.abstract The ability to spatially restrict specific activities across the cell cortex functionally defines individual cells and tissues. This is achieved, in part, via the assembly of protein complexes that link the plasma membrane to the underlying cortical actin cytoskeleton. The neurofibromatosis type 2 (NF2) tumor suppressor Merlin and closely related ERM proteins (Ezrin, Radixin and Moesin) are a special class of such membrane:cytoskeleton associated proteins that function to organize specialized cortical domains. In addition to their high degree of similarity, mounting evidence suggests that Merlin/ERMs share a functional relationship, which is largely unexplored. Unlike Merlin, the ERMs are not known to inhibit cell proliferation; in fact, Ezrin is thought to promote tumor metastasis. Defining the relationship between Merlin and the ERMs is essential to appreciating their respective roles in cancer development. Here I demonstrate a novel role for Merlin and the ERMs in generating cortical asymmetry in the absence of external cues. Our data reveal that Merlin functions to restrict the cortical distribution of Ezrin, which in turn positions the interphase centrosome in single epithelial cells and 3D organotypic cultures. In the absence of Merlin, ectopic cortical Ezrin yields mispositioned centrosomes, misoriented spindles and aberrant epithelial architecture. Furthermore, in tumor cells with centrosome amplification, the failure to restrict cortical Ezrin abolishes centrosome clustering, yielding multipolar mitoses. Consistent with a functional relationship, I observe a strong genetic interaction between Nf2 and Ezrin in the mouse intestine in vivo. Finally, I begin to address the basis of their functional interaction by testing whether they are coordinately regulated by the Ste-20 like kinase SLK. Altogether, these data uncover fundamental roles for Merlin/ERM proteins in spatiotemporally organizing the cell cortex in vitro and in vivo and suggest that Merlin’s role in promoting cortical heterogeneity may contribute to tumorigenesis by disrupting cell polarity, spindle orientation and potentially genome stability. en_US
dc.language.iso en_US en_US
dash.license LAA
dc.subject alpha-catenin en_US
dc.subject Cdk5 en_US
dc.subject ERM en_US
dc.subject Merlin en_US
dc.subject polarity en_US
dc.subject tumor suppressor en_US
dc.subject cellular biology en_US
dc.subject developmental biology en_US
dc.subject oncology en_US
dc.title Functional Relationship between Merlin and the ERM Proteins en_US
dc.type Thesis or Dissertation en_US
dc.date.available 2013-10-05T07:30:30Z
thesis.degree.date 2012 en_US
thesis.degree.discipline Cell and Developmental Biology en_US
thesis.degree.grantor Harvard University en_US
thesis.degree.level doctoral en_US
thesis.degree.name Ph.D. en_US
dc.contributor.committeeMember DeCaprio, James en_US
dc.contributor.committeeMember Hinds, Philip en_US
dc.contributor.committeeMember Danuser, Gaudenz en_US
dc.contributor.committeeMember Dyson, Nicholas en_US

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