Hyaluronan, RHAMM mediated signal transduction : functions in focal adhesion turnover, cell locomotion and tumorigenesis

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Hall, Christine L.
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Extracellular matrix (ECM) molecules and their receptors are important regulators of adhesion, migration, cytoskeletal organization, gene expression, growth and differentiation. Moreover, ECM receptors can serve to mediate signal transduction pathways that can influence, and sometimes direct, the events required for tumorigenesis. In particular, the extracellular matrix molecule hyaluronan (HA) has been associated with tumorigenesis, tumor cell migration, invasion and metastasis. Through the study of HA receptors, such as CD44 and RHAMM, the relationship between HA and tumor progression has changed from correlative to causative. This thesis addresses the role of one of these receptors, RHAMM (Receptor for HA Mediated Motility), in the regulation tumor cell locomotion and tumorigenesis. By examining the signal transduction pathways and cytoskeletal alterations involved in HA:RHAMM induced cell locomotion. this study has identified tyrosine phosphorylation within focal adhesions as a key event in the HA:RHAMMcell motility pathway; it has revealed a role for RHAMM in tumorigenesis; it has provided a functional link between RHAMM and two oncogene products, ras and src; and it has predicted that tyrosine phosphorylation and focal adhesion turnover play important roles in both cell locomotion and tumorigenesis. The results here are presented as a series of three papers: Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity, J. Cell Biol., 126:575-588, 1994: Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation, Cell, 82: 19-28, 1995; and pp60$\sp{{\rm c}-src}$ is required for cell locomotion regulated by the hyaluronan receptor RHAMM, Oncogene, in press, 1996. In combination, these results suggest a model in which HA and RHAMM are central players in the regulation of the actin cycle, cell motility and transformation.