Lessons Learned by Studying a Mucin-Dependent MAPK Pathway in a Model Fungal System

Organisms sense and respond to changes in the environment through signal transduction pathways. Pathways like highly conserved Mitogen-Activated Protein Kinase (MAPK) pathways are composed of sensor proteins, cytosolic relay proteins, and transcription factors. A mysterious feature of MAPK pathways is they contain common or shared components that function in multiple pathways. The question of signal specificity is important because mis-regulation of pathways, such as by cross talk, and cause diseases like cancer in humans. A priority is to understand how specificity is achieved between MAPK and other pathways that share components. A type of sensor protein for MAPK pathways are members of the mucin family of proteins. Mucins are highly glycosylated transmembrane proteins that function at the cell surface. In humans, mucins are mis-regulated in cancers, being markers for poor prognosis and targets of immunotherapies. Mucins remain poorly characterized because of their ill-defined mechano-sensory properties, the unknown effects of various types of glycosylation on signaling, and their poorly explored connections to cytosolic relay proteins. The lack of understanding in mucin biology is highlighted when compared to the common G-protein coupled receptors (GPCRs), whose ligands are well defined, structures resolved, and connections to effector proteins firmly established. In the genetic model yeast, two mucins regulate different MAPK pathways, providing an opportunity to define how mucins regulate signaling specificity. Mucins work with relay proteins including G-proteins like the Rho GTPase Cdc42. This regulator of signaling and polarity interacts with effector kinases to regulate MAPK pathways. We have identified a member of the Ral GDS family that binds Cdc42 and may direct it to a specific pathway. Because mucins, Ral GDS proteins and Cdc42 are conserved throughout eukaryotes, studying specificity mechanisms in a model system can teach us about related pathways important for human health.

Learning Objectives: 

1. Discuss how signaling mucins regulate MAPK pathways.

2. Demonstrate knowledge of signal specificity by scaffolds.

3. Demonstrate knowledge of signal integration in networks.