Recent studies in the areas of protein trafficking, growth factors, and tumor growth have suggestd an important link between lysosomal enzyme secretion and cell growth. As a long term approach toward understanding this link, this laboratory has been examining lysosomal protein trafficking and function in mouse 3T3 fibroblasts. Previous studies have shown that synthesis and secretion of lysosomal, mannose 6-phosphate-containing proteins are regulated in these cells under various conditions of cell growth. These proteins include "MEP", the major excreted protein of transformed fibroblast cell lines, and proliferin, the major serum-induced protein secreted by untransformed fibroblasts. On the basis of their patterns of regulation, it appears likely that extracellular forms of these proteins play important roles in the process of normal cell growth. These proteins may participate directly in the growth process by acting as autocrine or paracrine growth factors, or indirectly through modification of cell surface receptors or components of the extracellular matrix. The proposed studies will involve characterization of the synthesis and trafficking of proliferin, and examination of the function of MEP and proliferin as growth regulators or modifiers of the extracellular matrix. Functional studies will involve the use of antisense RNAs and other inhibitors to inactivate MEP and proliferin in growing cells. The results of these studies should increase our understanding of how and why lysosomal trafficking is regulated during cellular growth, and, in turn, how lysosomal proteins released from cells may be involved in cell growth regulation.
