The goals of this project are to elucidate the mechanisms of action of tumor viruses and to determine the cellular alterations responsible for naturally occurring malignancies. Some of the highlights of the past year include: (1) characterization of the keratinocyte growth factor (KGF) as fibroblast growth factor (FGF)-related with properties of a paracrine effector of epithelial cell growth; (2) the epidermal growth factor (EGF) receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signalling: (3) v-sis-transformation requires cell surface localization of internally activated growth factor receptors: (4) isolation and characterization of erbB-3, a third member of the erbB/EGF receptor family which is found to be overexpressed in a subset of human mammary tumors: (5) discovery that the complete coding sequence of abl-2 defines the abelson subfamily of cytoplasmic tyrosine kinases; (6) mapping and dissociation of the potent transforming and secretory properties of PDGF A and PDGF B; (7) immunochemical localization of the epitope for a monoclonal antibody that neutralizes human PDGF mitogenic activity; (8) independent expression of human alpha or beta PDGF receptor cDNAs leads to functional coupling with mitogenic and chemotactic signaling pathways; (9) PDGF induces tyrosine phosphorylation of GTPase activating protein; (10) generation of fibrosarcomas by a retrovirus that expresses the normal B chain of PDGF and mimics the alternative splice pattern of the v-sis oncogene; (11) development of an efficient method to construct eukaryotic expression of cDNA libraries; (12) autocrine interaction between TGFalpha and the EGF receptor; (13) demonstration that the N-terminal region of proto-dbl down-regulates its transforming activity; and (14) CSF-1 induction of proliferation, chemotaxis and reversible monocytic differentiation in myeloid progenitor cells transfected with the human c-fms/CSF-1 receptor cDNA.
