Understanding morphogenesis and tumorigenesis
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 such as cell:cell and cell:matrix adhesions, the intestinal brush border, neuronal growth cone and immunological synapse. The assembly of such cortical domains involves the coordination of processes occurring at the plasma membrane with those in the underlying cytoskeleton. Central to this coordination is the formation of protein complexes at the plasma membrane that position membrane receptors, control their abundance and activity, and link them to the cortical cytoskeleton, thereby serving both regulatory and architectural functions. The overarching goal of my laboratory is to understand how the organization of protein complexes at the cell cortex contributes to morphogenesis and tumorigenesis.
This interest stems from a longstanding dedication to elucidating the molecular basis of neurofibromatosis type 2 (NF2), a familial cancer syndrome that is caused by mutation of the NF2 tumor suppressor gene. The NF2-encoded protein Merlin is closely related to the ERM proteins (Ezrin, Radixin and Moesin) that link membrane proteins to the cortical cytoskeleton, thereby both stabilizing membrane complexes and stiffening the cell cortex. The proximal goal of our work is to delineate the molecular function of Merlin and identify therapeutic targets for NF2; our work also directly addresses fundamental aspects of basic and cancer cell biology.
Through the generation and analysis of mouse and three dimensional tissue culture models, we identified critical roles for Merlin and the ERM proteins in morphogenesis, homeostasis and tumorigenesis in many tissues including the liver, kidney, intestine, skin and mammary gland. Molecular and cell-based studies suggest that these phenotypes are caused by defective organization of the cortical cytoskeleton, which leads to altered distribution of membrane receptors such as EGFR/ErbBs, cell junction components, and/or protein complexes that guide the orientation and function of the mitotic spindle. We also discovered that a fundamental function of Merlin is to restrict the distribution of Ezrin at the cell cortex and that loss of this activity underlies several of these phenotypes. In the absence of Merlin, unrestricted cortical Ezrin drives aberrant mechanical stress on cell-cell junctions, altered endocytic trafficking of membrane receptors and abnormal centrosome-to-cortex communication, yielding defective spindle orientation and integrity. These studies provided novel insight into how the organization of the cell cortex governs the identity and behavior of individual cell types and into how defective cortical organization contributes to unscheduled cell proliferation, invasion and tumor development.
Ongoing studies extend both basic and translational implications of this work. We have uncovered new mechanistic insight into how Merlin/ERMs organize the biochemical and physical properties of the cell cortex and how this, in turn, controls receptor distribution and spindle orientation/integrity. Importantly, we are also pursuing novel translational avenues that stem directly from our basic studies by delineating the role of unregulated: ErbB signaling and aberrant centrosome/spindle function in NF2-mutant tumors. Indeed, we have found that NF2-mutant tumor cells exhibit altered ErbB trafficking and centrosome/spindle integrity and sensitivity to drugs that target each.
We believe that the continued partnering of discovery-based science and translational studies will not only lead to novel therapeutic options for NF2-mutant tumors but also advance our understanding of these basic cellular activities that are known to contribute to other human cancers.
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Image: McClatchey Lab
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Image: McClatchey Lab
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Image: McClatchey Lab
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Image: McClatchey Lab
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Image: McClatchey Lab
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Image: McClatchey Lab