Signaling Mucin-Dependent MAPK Activation In A Model Eukaryote
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Cellular processes are regulated by signal transduction pathways and elicited by the activation of cell-surface receptors. A class of receptors called cell adhesion proteins or signaling mucins activates signal transduction pathways. Signaling mucins also mediate the reorganization of cell polarity during oncogenesis. It is unclear how signaling mucins participate in cellular signaling pathways, and how they restructure cell polarity. To better understand the role of signaling mucins in these cellular processes, I have investigated the role of a yeast signaling mucin, Msb2, in activating the filamentous growth MAPK pathway. We found that the extracellular domain of Msb2 is processed by an aspartyl protease, Yps1. The cleavage of Msb2 generates an active form of the protein, which functions through Sho1, cell-surface regulatory protein, to activate MAPK pathway. In addition to its role in intracellular signaling, cytoplasmic tail of Msb2 is down-regulated by ubiquitination in an Rsp5-dependent mechanism. Based on our findings, we have identified a cleavage-dependent activation mechanism for Msb2. I also explored the relationship between filamentous growth and the cell polarity pathway. We uncovered that under the rich-nutrient conditions, the bud-site-selection proteins through their association with the Cdc42 GTPase module regulate the activation of the filamentous growth pathway. Moreover, Msb2 and Sho1 induce cell polarization independent of the filamentous growth pathway components. The cytoplasmic tail of Msb2 binds a cell polarity component, Cap2 and through this association Msb2 reorganizes cell polarity during filamentous growth. Overall this work provides a general mechanism of how mucins can regulate MAPK pathways.