The ultimate goal of this work is to determine how the control of cell shape and cell proliferation is regulated by interactions between cells and their extracellular matrix, and how this control is altered in pathological situations. An understanding of this regulation requires identifying the components involved in these cell-matrix interactions. My prior work has elucidated a potential candidate for being involved in these interactions, a heparan sulfate proteoglycan at the surface of mouse mammary epithelial cells. Initial studies suggest that the proteoglycan is an integral plasma membrane protein and that it binds components of both the extracellualr matrix and of the cytoskeleton. This work has led to the hypotheses that the membrane proteoglycan may serve as a vehicle by which the matrix stabilizes the cytoskeleton and/or as an intermediate in the secretion of extracellular proteoglycan. I shall pursue these hypotheses by (i) isolating and purifying the membrane proteoglycan, preparing antibodies and characterizing it molecularly, (ii) evaluating its kinetic and structural relationships to extracellular proteoglycans, (iii) assessing its interaction with actin filaments and (iv) examining its binding to various matrix components. This work impinges directly on how the extracellular matrix, the in vivo substratum, regulates cell shape and cell proliferation and how this regulation is modified in pathological situations. Specifically, knowledge of the elements involved in this regulation is required to develop rational means of preventing the abnormalities in organ morphogenesis that lead to birth defects as well as the defective control of growth and tissue integrity that underly neoplastic invasion and metastasis.
