The neu oncogene encodes a tyrosine kinase with growth factor receptor-like properties. A neu proteinspecific activating factor (NAF) was partially purified from medium conditioned by the transformed human T-cefl line ATL-2. NAF was able to stimulate the tyrosine-specific kinase activity of the neu protein (p185"), induce dimerization and internalization, and increase the growth ofcells bearing the neu protein. The effects of NAF were mediated by an interaction with the pl85" extracellular domain. NAF had no effect on the epidermal growth factor receptor kinase activity and no effect on cells that express that receptor. Further analysis of NAF and of other recently described neu protein-activating activities should help clarify the role of the neu protein in cell growth and transformation.The rat neu gene encodes a 185-kDa transmembrane tyrosine kinase that shows significant structural similarity to the epidermal growth factor receptor (EGFR) (1-3). The rat neu gene product has been identified in two forms: the protooncogenic form is termed pl85-cneu and the oncogenic form is termed p185neu. pl8Snu becomes activated in chemically induced neuroglioblastomas by a point mutation in the transmembrane region that results in constitutively increased neu tyrosine kinase activity (4-7). The c-erbB-2 gene (8, 9) is the human homologue of the rat neu gene, and aberrant c-erbB-2 protein expression has been implicated in a number of human adenocarcinomas, including those of the breast (10-12), ovaries (12), salivary gland and digestive tract (13), skin (14), kidney (13), pancreas (15), and lung (16). Its growth factor receptor-like attributes, tissue-specific and developmentally regulated expression pattern (17,18), and involvement in neoplasia suggest that the pl85/c-erbB-2 protein plays a role in normal and abnormal growth and differentiation ofthe cells in which it is expressed and that a cognate ligand exists for this protein.Although the neu gene has been studied for nearly 10 years now, identification of candidate ligands for p185 have only been reported in the last 2 years. Though several endogenous p185 modulatory factors may exist, the effects of the ligand for p185 might be most comparable to those of EGF and platelet-derived growth factor (PDGF) on their receptors, since these receptors are the transmembrane tyrosine kinases most closely related to p185 (19,20). According to these criteria, the primary ligand for p185 should increase the autophosphorylation/kinase activity of p185, induce p185 dimerization and internalization, and affect the growth of cells that express p185. Several reports have described preparations that contain p185-activating activity (21-23). Each of these activities/factors conforms to these criteria to a different extent. We report here the characterization of a purified neu protein-specific activating factor (NAF) secreted by the transformed human T-cell line ATL-2 (24) that meets all of these expected criteria. MATERIALS AND METHODSCells. PN-NR6 and PT-NR6 cells express high lev...

Twelve cases of gastric submucosal tumours, originally diagnosed as leiomyoma and leiomyosarcoma, were investigated by staining with the neurogenic markers S-100 and neuron specific enolase (NSE). Three cases were, in addition, studied by electron microscopy. The tumours stained negatively for desmin, indicating that they were not of smooth muscle origin. All stained positively for S-100 and NSE. The ultrastructural features in the cases examined by electron microscopy were reminiscent of autonomic nerve structures normally present in the gastric wall. These included fine cytoplasmic processes of Schwann cells, wrapped with complete or incomplete basement membranes, and structures analogous to post-ganglionic neuroaxonal components. These tumours appear to represent a distinct type of gastric neoplasm originating from autonomic nerve elements in the stomach wall. They are different from previously described schwannomas or neurofibromas. In some of the tumours, identifiably neural elements are relatively a minor component, and the majority of the tumour cells are of undetermined origin. It is suggested that these cells may be poorly differentiated, lacking their antigenic determinants specific to neural differentiation.

The aim of our study was to investigate the relationship between gastrin producing cell density with antral mucosa, luminal and serum gastrin concentration in antral atrophic gastritis. Our study group consisted of 17 patients: six with mild atrophic gastritis, seven with moderate atrophic gastritis and four with severe atrophic gastritis. None of the patients had type-A atrophic gastritis but the body mucosa was affected by superficial gastritis at various extent in some. A group of 15 healthy subjects served as control. AlU subjects underwent gastroscopic examination with multiple bioptic sampling. Radioimmunoassay was used for gastrin determination and photomicroscopy for gastrin producing cell density assessment. Electron microscopy was used to assess the gastrin producing granule density index. Patients with moderate and severe atrophic gastritis showed a lower gastric acidity and acid output as compared to control. Serum gastrin did not show significant differences among the groups. In moderate and severe atrophic gastritis, gastrin producing cell granule density index, gastrin producing cell density and antral mucosa gastrin concentration were significantly lower when compared with control and decreased with advancing of the severity of atrophic gastritis. In atrophic gastritis, however, the latter two measurements were not correlated. In moderate and severe atrophic gastritis luminal gastrin concentration significantly increased, compared with control, after the severity of atrophic gastritis. Gastrin producing cell granule density index and luminal gastrin concentration showed a significant correlation with gastric pH. These data suggest that in antral atrophic gastritis with reduced gastric acidity, the decrement of gastrin producing cells is followed by gastrin producing cell hyperfunction with increased luminal release of gastrin.There have been several studies investigating the relationship between the counts of gastrin producing cells with serum gastrin concentration and/or gastric acid secretions.' It is often difficult to apply these data to atrophic gastritis, however, in which the distribution of gastrin producing cell has been reported to vary considerably.4"The purpose of our study was to study the interrelationships between antral gastrin producing cell density and gastrin concentration in antral mucosa, gastric juice and serum of patients with antral atrophic gastritis and low gastric acid output. Methods PATIENTSThe study group consisted of 17 patients (10 men, seven women; mean age 49 years, range 41-62) with biopsy proven antral atrophic gastritis. In all these patients, type-A gastritis had been previously ruled out, however, superficial gastritis in the body, and in some cases in the fundus too, had been recently documented. According to Whitehead's classification6 these cases were classified as six mild atrophic gastritis, seven moderate atrophic gastritis and four severe atrophic gastritis. The presence of gastric or duodenal ulcer constituted exclusion criteria. Fifteen subj...

Autophosphorylation of type I receptor tyrosine kinases (RTKs) comprises one step in the signaling events mediated by erbB receptors such as p185 neu and EGFR. Previous analysis of p185 neu has indicated that there are at least ®ve tyrosine autophosphorylation sites, Y882, Y1028, Y1143, Y1226/7 and Y1253, of which Y882 might be important because of its location in the kinase activity domain. We have speci®cally analysed the e ect of a Y882F (phenylalanine substituted for tyrosine at position 882) mutation in the enzymatic active domain. We also deleted the carboxyl terminal 122 amino acids which contained three other autophosphorylation sites (TAPstop) and combined mutants of that deletion with Y882F (Y882F/APstop). Both in vitro and in vivo transformation assays showed that substitution of tyrosine 882 by phenylalanine signi®cantly decreased the transforming potential of activated, oncogenic p185 neu , although no signi®cant di erence in the total phosphotyrosine levels of the mutant proteins were observed. To analyse mitogenic signaling in response to ligand, the intracellular domains of p185 neu and Y882F were fused with the extracellular domain of the EGF receptor. The proliferation of cells expressing these chimeric receptors was EGF-dependent, and cells expressing EGFR/Y882F chimeric receptors were less responsive to EGF stimulation than those expressing EGFR/neu receptors. In vitro kinase assays demonstrated that abolishing the autophosphorylation site Y882 diminished the enzymatic tyrosine kinase activity of p185 neu . These studies, taken together with the phenotypic inhibition observed with cells expressing Y882F, suggest that the tyrosine 882 residue may be important for p185 neu -mediated transformation by a ecting the enzymatic kinase function of the p185 neu receptor.

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