Cell migration is critical for metazoan development. In addition to its importance in development, cell migration is an important component of human diseases such as cancer. Metastasis is an active process in which cancerous cells migrate to new sites to form tumors. Metastatic cells utilize many of the same proteins as other migrating cells. The mechanisms by which migrating cells are directed to their proper positions is poorly understood. The long term goal of this project is to understand how migrating cells recognize and respond to the cues that direct their migrations. To investigate cell migration, the principal investigator has identified a Caenorhabditis elegans gene, cam-1, required for cells to migrate to their proper positions. In cam-1 mutants, several migratory cells are shifted anteriorly in their final positions. In addition, the orientation of cell polarity is disrupted. Cam-1 encodes a receptor tyrosine kinase (RTK) related to vertebrate and fly Ror RTKs. Ror proteins are RTKs of unknown function that are expressed in the developing nervous system. Overexpression and loss of cam-1 function result in reciprocal cell migration phenotypes. The data suggest that CAM-1 responds to an anteriorly expressed repulsive cue, a model the experiments in this application are aimed at testing. Cam-1 is expressed in the cells affected in mutants and cam-1 functions autonomously in cells that migrate. The experiments described in this application address the mechanism of CAM-1 function both in cell migration and in cell polarity. To achieve this goal, the principal investigator will take advantage of the simple genetics and morphology offered by C. elegans. Specifically, the principal investigator proposes to address five questions: 1) Do levels or spatial regulation of CAM-1 activity regulate cell migration and orient cell polarity?, 2) What are the extracellular cues that direct migrating cells and orient cell polarity?, 3) Is the kinase domain required for CAM-1 function?, 4) How does CAM-1 transmit its signal? and 5) How does cam-1 interact with the egl-20/Wnt signaling pathway? These experiments will identify new components of the cam-1 pathway and suggest testable models by which CAM-1 may act.
