Defects in cell morphogenesis promote the onset of diseases such as cancer and neurological disorders. Loss of cell polarity and disruption of tissue architecture is a common histological feature in cancer, playing an important role in the alteration of tissue organization. Although substantial progress has been made, the molecular mechanisms coordinating cell morphology and cell growth are still poorly understood. The long- term goal of our laboratory is to understand the cellular functions that govern cell shape emergence, 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. We have previously discovered that fission yeast NDR kinase Orb6 spatially regulates the activity of Cdc42 GTPase, a key morphology control factor. Recently, we have shown that Orb6 kinase also negatively regulates mRNA degradation and translational repression, promoting polarized cell growth. Using genomic-scale and proteomic approaches we have identified novel targets of Orb6 kinase, and discovered a novel role for Orb6 kinase in promoting cell adaptation and chronological lifespan during quiescence. The objective of this project is to define the mechanisms whereby NDR kinase spatially regulates cell shape, promotes cell growth and foster cell resilience in both yeast and human cells.
In Specific Aim1, we will define how NDR kinase phosphorylates key substrates to enable cell shape emergence.
In Specific Aim2, we will determine how NDR kinase regulates specific mRNA binding proteins to control polarized cell growth.
In Specific Aim3, we will establish the role of NDR kinase in enabling alternative physiological states, from active cell growth to cell quiescence, to promote cell resilience.
The conserved NDR kinase is an enzyme that controls cell shape and cell growth in many organisms ranging from yeast to mammals. Studies have shown that NDR kinase protein levels decrease in gastric cancer and lymphoma. Loss of NDR kinase has also been linked to defects in cardiac and neuronal cell function. 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 therapeutic targets in the treatment of disease.
