A wide variety of human tumors contain an amplified or overexpressed erbB-2 gene, which encodes a growth factor receptor-like protein. When erbB-2 complementary DNA was expressed in NIH/3T3 cells under the control of the SV40 promoter, the gene lacked transforming activity despite expression of detectable levels of the erbB-2 protein. A further five- to tenfold increase in its expression under influence of the long terminal repeat of Moloney murine leukemia virus was associated with activation of erbB-2 as a potent oncogene. The high levels of the erbB-2 product associated with malignant transformation of NIH/3T3 cells were observed in human mammary tumor cells that overexpressed this gene. These findings demonstrate a new mechanism for acquisition of oncogenic properties by genes encoding growth factor receptor-like proteins and provide a functional basis for the role of their overexpression in the development of human malignancies.

A genomic sequence and cloned complementary DNA has been identified for a novel receptor-like gene of the PDGF receptor/CSF1 receptor subfamily (platelet-derived growth factor receptor/colony-stimulating factor type 1 receptor). The gene recognized a 6.4-kilobase transcript that was coexpressed in normal human tissues with the 5.3-kilobase PDGF receptor messenger RNA. Introduction of complementary DNA of the novel gene into COS-1 cells led to expression of proteins that were specifically detected with antiserum directed against a predicted peptide. When the new gene was transfected into COS-1 cells, a characteristic pattern of binding of the PDGF isoforms was observed, which was different from the pattern observed with the known PDGF receptor. Tyrosine phosphorylation of the receptor in response to the PDGF isoforms was also different from the known receptor. The new PDGF receptor gene was localized to chromosome 4q11-4q12. The existence of genes encoding two PDGF receptors that interact in a distinct manner with three different PDGF isoforms likely confers considerable regulatory flexibility in the functional responses to PDGF.

The ErbB/HER family of receptor tyrosine kinases consists of four receptors that bind a large number of growth factor ligands sharing an epidermal growth factor-(EGF)-like motif. Whereas ErbB-1 binds seven di erent ligands whose prototype is EGF, the three families of neuregulins (NRGs) activate ErbB-3 and/or ErbB-4. Here we characterize a fourth neuregulin, NRG-4, that acts through ErbB-4. The predicted pro-NRG-4 is a transmembrane protein carrying a unique EGF-like motif and a short cytoplasmic domain. A synthetic peptide encompassing the full-length EGF-like domain can induce growth of interleukin-dependent cells ectopically expressing ErbB-4, but not cells expressing the other three ErbB proteins or their combinations. Consistent with speci®city to ErbB-4, NRG-4 can displace an ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor. Expression of NRG-4 mRNA was detected in the adult pancreas and weakly in muscle; other tissues displayed no detectable NRG-4 mRNA. The primary structure and the pattern of expression of NRG-4, together with the strict speci®city of this growth factor to ErbB-4, suggest a physiological role distinct from that of the known ErbB ligands.

The objective of the study was (1) to measure systematically the orientation, morphology, and population density of endothelial nuclei of the canine thoracic aorta and its major branches and (2) to obtain evidence in a chronic in vivo preparation that altered flow patterns do indeed change patterns of nuclear orientation. For this purpose, a segment of the descending thoracic aorta was removed, opened longitudinally, and reclosed to form a tube with a new longitudinal axis 90° from the original vessel axis. The new segment was then sutured back in place. The animals were killed at suitable postoperative periods. Endothelial nuclear patterns were studied from en face photomicrographs of preparations stained with Evans blue dye. Results indicated: (1) In uniform vessel segments, e.g., middle and lower descending thoracic aorta, the nuclei were oriented parallel to the axis of the blood vessel, and the ratio of major to minor axes of the nucleus was large. The flow in these regions is known to be stable. (2) Nonaxial, less-ordered nuclear orientation with smaller ratios of major to minor axes were found in entrance regions of many major arteries and in the ascending aorta. (3) In chronic studies in which the flow pattern was altered, the nuclear pattern realigned in the direction of flow within 10 days after surgery. stresses produced by blood flow in the arterial tree.Previous histologic studies have demonstrated that nuclei of endothelial cells in large arteries are ellipsoidal and are oriented in an orderly fashion with their long axes aligned with the major axis of the vessel. Studies in which the endothelial cell borders have been stained with silver and viewed en face have shown that the cells are also uniform in size, shape, and orientation (4). Variations in size and orientation of endothelial nuclei and the presence of multinucleated cells have been correlated qualitatively with age in rats (5) and in man (6), and severity of atherosclerosis in man (7), exposure to x-rays in rabbits (8), and endothelial regeneration in rabbits Diagram of method for measurement of orientation and the ratio of major to minor axes of endothelial nuclei. A: Arterial segment opened parallel to longitudinal axis of vessel. B: Opened vessel mounted in plane parallel to microscope stage. C: Schematic photomicrograph of endothelial nucleus. i = angle of orientation of major axis of nucleus with reference to longitudinal axis of vessel; a = major axis of nucleus; bminor axis of nucleus.