HER2, the erbB-2/neu proto-oncogene product, is a 185-kDa transmembrane glycoprotein related to the epidermal growth factor receptor. Overexpression of HER2 was reported in several human adenocarcinomas, including mammary and ovarian carcinomas. A family of glycoproteins, the heregulin/neu differentiation factors, was characterized and implicated as the ligands for HER2. Recently, it has been shown that HER2 alone is not sufficient to reconstitute high affinity heregulin receptors and that HER3 or HER4 may be the required components of the heregulin receptors on mammary carcinoma cells (Sliwkowski, M. X., Schaefer, G. A family of EGF 1 receptor-related proteins has recently been described that includes the proto-oncogene products of erbB-2/ neu (HER2), erbB-3 (HER3), and erbB-4 (HER4) (1, 2), which have a high degree of sequence homology (40 -50%) and similar molecular structure, containing a glycosylated extracellular domain, a transmembrane domain, and a conserved tyrosine kinase domain. The HER2 receptor was the first of these discovered by two groups who screened human genomic libraries at low stringency using EGF receptor-based probes (3, 4). Subsequent to this, the HER3 (5) and HER4 (6) receptors were identified using similar techniques. Despite the structural similarity between these receptors, they have no binding affinity for any of the EGF ligands, which leaves open the possibility that ligands exist for each of these receptors.The identity of the ligands for these receptors has been the object of much investigation resulting in the identification of several candidate ligands for HER2. A 30-kDa protein (7) and heregulin (8) were purified from the conditioned medium of MDA-MB-231 mammary carcinoma cells. Neu differentiating factor was purified from the conditioned medium of ras-transformed fibroblasts (9), and Neu activating factor was purified from the conditioned medium of human ATL-2 T cells (10). Each of these putative ligands was shown to activate phosphorylation of the HER2 protein, p185. Subsequent to the cloning of Neu differentiating factor (11) and heregulin (8), peptide ligands with a high degree of sequence homology with heregulin/Neu differentiating factor, the glial growth factors-I, -II, and -III (12) and a protein that stimulates muscle acetylcholine receptor synthesis (ARIA) (13) were identified. These findings indicate that a family of heregulin-like ligands exist that are important in the development and regeneration of the nervous system and are products of the same gene, produced by alternatively spliced mRNA (12,13).Whether the heregulin/Neu differentiating factor is truly a ligand for HER2 was recently disputed by the finding that heregulin did not activate phosphorylation of p185 in ovarian cell lines expressing HER2 and in ovarian cells transfected with HER2 (14). These results suggest that another component in addition to HER2 is required for the heregulin receptor. More recently, both HER4 (16) and HER3 (17, 18) have been separately reported to be the additional component requ...

Activation of CD4+ T cells by antigenic peptide involves the interaction of major histocompatibility complex (MHC) class Il-peptide complexes on the surface of antigen-presenting cells (APCs) with T-cell receptors. This report describes the kinetics of T-cell triggering by exogenous antigenic peptides in the presence of APCs. A rapid specific increase in extracellular acidification rate is observed within minutes upon exposure of A.E7 T cells (restricted for IEk and moth cytochrome c peptide containing residues 88-103) and 4R3.9 T cells {restricted for IAk and myelin basic protein peptide containing residues 1-14 [AcMBP-(1-14)]} to their cognate peptides in the presence of CH27 cells bearing both TAk and IEk MHC class II molecules. Pretreatment of cloned T cells, but not APCs, with herbimycin A resulted in complete inhibition of triggering events, indicating that the acidification response is mediated by T-cell second messenger pathways. This rapid assay for 4R3.9 T-cell stimulation showed increased T-cell triggering activity for AcMBP-(1-14)-A4 and MBP-(1-14)-M4 peptides compared to the native AcMBP-(l-14)-K4. By using the previously determined kinetic constants for MBP-(1-14)-A4 reactions with TAk, it is possible to show that at the lowest peptide concentrations the kinetics of T-cell triggering are limited by the kinetics of the peptide binding to MHC class II molecules.The specific response of T-helper (TH) lymphocytes to peptide antigens normally requires the participation of antigenpresenting cells (APCs) bearing class II molecules of the major histocompatibility complex (MHC) on their surfaces. A minimal requirement for TH triggering is that a molecular complex (Mp) of peptide (p) and the class II molecule (M) form a trimolecular complex with the T-cell receptor (MpR). These trimolecular complexes are localized at the interface of T-cell and APC membranes. There is substantial interest in the physical chemical properties of these complexes. For example, it has been proposed that the avidities of class II moleculepeptide complexes for the T-cell receptor play a central role in positive and negative selection in the thymus and in the periphery (1). Another proposal is that weak binding of antigenic peptides to MHC class II molecules enables autoreactive T cells to escape negative selection and, thus, correlates weak binding to a number of autoimmune diseases (2, 3).The two binding reactions can be represented schematically by the equilibria [1] M + p = MP.Mp + R MpR.The equilibrium (dissociation) constants K1 and K2 are then relevant to the above proposals.[3] [4] In the present work, we show that insight into the role of these reactions in specific TH triggering is achieved through measurements of this triggering at short times and low peptide concentrations. The parameter used to quantitate the early cellular response to T-cell triggering in the presence of APCs and antigenic peptide is the extracellular acidification rate as measured by a microphysiometer (4-6). Our analysis of these results requ...

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Nitrosylbromid reagiert mit der Aminosäure (I) zur α‐Bromcarbonsäure (II), die mit Mercaptoethyl‐amin (III) zu (IV) substituiert wird.

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