Andrea I. McClatchey
The vast array of forms and functions exhibited by different cell types is made possible by the organization of specialized domains within the cell cortex. The overarching goal of our laboratory is to understand how the organization of protein complexes at the cell cortex contributes to morphogenesis and tumorigenesis/metastasis. Cortical protein complexes position membrane receptors, control their abundance/activity and link them to the cytoskeleton, thereby serving both regulatory and architectural functions. Our studies are focused on the NF2 tumor suppressor, Merlin and the closely related ERM proteins (Ezrin, Radixin and Moesin) that link membrane proteins to the cortical actin cytoskeleton and are key architects of the cell cortex.
Inherited mutation of the human NF2 gene underlies the familial cancer syndrome neurofibromatosis type 2, which features the development of nervous system tumors. Through the generation and analysis of mouse models we have identified critical roles for Merlin and the ERMs in morphogenesis, homeostasis and tumorigenesis in several tissues including the liver, kidney, intestine, skin and mammary gland. Our work suggests that these phenotypes reflect the defective assembly and distribution of cortical protein complexes that contain receptors (ie EGFR), polarity proteins (ie Par3), and/or cell junction components. Our molecular studies suggest that Merlin/ERMs are designed to simultaneously create a specific physical cortical environment and link certain receptors/membrane proteins to it, thereby controlling fundamental processes such as receptor endocytosis, cell adhesion, polarity and spindle orientation. Indeed, our most recent studies have uncovered complementary roles for Merlin and Ezrin in organizing the cortex of single cells.
Each of our mouse models reflects a unique biological context for studying how cortical organization defines the identity and behavior of individual cell types. Conversely, the study of each of these models will yield new insight into how aberrant cortical organization contributes to unscheduled cell proliferation and tumor development/ progression. As we continue to define the molecular function of Merlin and the ERMs we are using this information to develop therapeutic strategies and test them in cell-based assays and preclinical mouse models of Nf2-associated tumor development.
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