Control of cell morphogenesis and cell growth by conserved NDR kinase Orb6

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DESCRIPTION (provided by applicant): Cell polarity is essential for cell morphogenesis, cell migration, and for normal tissue architecture. It involves the dynamic coordination of many cellular processes such as cytoskeletal polymerization, protein synthesis and membrane trafficking. Although substantial progress has been made in our understanding of cell morphogenesis, many of the molecular mechanisms involved in this process are still unknown. The long-term goal of our laboratory is to understand the cellular functions that govern cell shape, and in particular the signaling networks that coordinate cell polarity with cell growth. The conserved NDR kinase plays a key role in the control of cell morphology and cell proliferation in several organisms ranging from yeast to mammals. Currently, there is a very limited understanding of the cellular functions of this conserved kinase and of its targets in the control of cell morphogenesis. We have recently discovered a role for the fission yeast NDR kinase Orb6 in the spatial control of Cdc42 GTPase, a key morphology control factor. Using both hypothesis-driven studies as well as genomic-scale and proteomic approaches; we will dissect the function of Orb6 kinase and identify its targets in the control of cell morphogenesis. The objective of this project is to define the mechanisms whereby NDR kinase spatially regulates cell shape. PUBLIC HEALTH RELEVANCE: Loss of cell polarity and disruption of tissue architecture is a common histological feature in cancer, and emerging evidence is revealing a key role of cell polarity control pathways in the alteration of tissue organization during tumorigenesis. The results of this research project will provide insight into a novel signaling pathway with a conserved function in the control of cell morphogenesis. PUBLIC HEALTH RELEVANCE: The conserved NDR kinase is an enzyme that controls cell shape in many organisms ranging from yeast to mammals. Recently NDR kinase has been recognized as a novel tumor suppressor. Loss of human NDR kinase expression has been detected in T cell lymphoma, gastric tumor and prostate tumor samples. The mechanism by which NDR kinases controls cell shape and cell growth is not known. This project proposes to study the cell shape and cell growth functions of NDR kinase with the long-term goal to identify novel diagnostic markers or novel therapeutic targets in the treatment of cancer.