Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A molecule that is immunologically related to the c-erbB-2 oncogene product (p185HER2/neu) was detected in the conditioned culture medium from neu-overexpressing tumor cell lines and in sera of advanced-stage breast carcinoma patients. Using a sensitive (in the range of 0.5 ng ml-1) double-determinant radioimmunoassay (DDIRMA) with two monoclonal antibodies (MAbs) directed against the neu extracellular domain (ECD), soluble oncoproteins were detected in supernatants from several neu-positive tumor cell lines, independent of the levels of membrane p185HER2 expression. The molecule detected did not react with a MAb directed against an intracytoplasmic epitope of the p185HER2. Western blot analysis of the concentrated supernatant revealed a protein of approximately 110 kDa molecular mass, which closely matches the predicted size of the glycosylated p185HER2 ECD. Immunoprecipitation of culture supernatant from cell surface-radioiodinated cells confirmed the 110 kDa molecular mass of the glycosylated shed protein, which migrated to 86 kDa after deglycosylation. Proteolytic cleavage of the p185HER2 molecule was demonstrated in release assays carried out with protease inhibitors. The combined use of leupeptin and EDTA completely inhibited release of the molecule. Analysis of sera from breast carcinoma patients and healthy donors by DDIRMA revealed the presence of soluble neu in 15% of pathologic sera but none of the normal sera. A good correlation was found between neu-overexpression in the primary tumor and the soluble marker in serum of patients with advanced disease; sera of early-stage patients were always negative, independent of neu-overexpression in the tumor. These results suggest the usefulness of soluble neu as an indicator of tumor aggressiveness but not as a diagnostic marker of breast cancer.
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PMID:The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage. 810 38

The c-neu oncoprotein, p185c-neu, is a transmembrane tyrosine kinase that shares structural similarities with the receptor for epidermal growth factor (EGFr). We used immunoblots, immunoprecipitation, and immunohistochemistry 1) to test the hypothesis that p185c-neu and EGFr are coordinately expressed in central nervous system tissue and 2) to assess the spatiotemporal expression of both the c-neu oncoprotein and EGFr in the rostral cerebral cortex. In nondenaturing gels, anti-c-neu antibody identified high molecular weight proteins (about 300-400 kDa) that were reduced by EDTA to a molecular weight of 180-200 kDa. Sodium dodecylsulfate polyacrylamide gel electrophoresis broke down this protein into an array of smaller peptides, which were expressed prenatally, transiently during the first three postnatal weeks, or in the adult. Perinatally, c-neu immunoreactivity was evident in subplate neurons, ascending processes of neurons in the cortical plate, and ventricular zone cells. During the second postnatal week, cells throughout cortex expressed somatodendritic immunostaining, but, in the adult, c-neu immunoreactivity was expressed only by pyramidal neurons in layer V and by glia in the white matter and ependyma. EGFr-positive proteins behaved in the nondenaturing gels as did c-neu-positive oncoproteins, suggesting that both proteins naturally formed dimers. This contention was supported by the EGFr-or c-neu immunolabeling of tissue that was previously immunoprecipitated with anti-c-neu or anti-EGFr, respectively. The pattern of EGFr immunolabeling in the developing and mature cortex was virtually identical to that described for c-neu immunoreactivity. Cortical neurons express the c-neu oncoprotein and EGFr, probably as heterodimers. The specific immunolabeling of layer V neurons in the adult cortex with anti-c-neu and anti-EGFr suggests that the p185c-neu ligand and EGF regulate the activity of corticofugal systems. The expression of different c-neu- and EGFr-positive peptides is developmentally defined and may be related to specific ontogenetic events.
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PMID:c-neu oncoprotein in developing rostral cerebral cortex: relationship to epidermal growth factor receptor. 886 25

HER2/neu, a Mr 185,000 tyrosine kinase receptor that is overexpressed in breast cancer, undergoes proteolytic cleavage of its extracellular domain (ECD). In contrast with other membrane-bound proteins, including growth factor receptors, that are cleaved by a common machinery system, we show that HER2 cleavage is a slow process and is not activated by protein kinase C. Pervanadate, a general inhibitor of protein-tyrosine phosphatases, induces a rapid and potent shedding of HER2 ECD. The shedding of HER2 ECD is inhibited by the broad-spectrum metalloprotease inhibitors EDTA, TAPI-2, and batimastat. The tissue inhibitor of metalloproteases-1; an inhibitor of matrix metalloproteases that does not inhibit cleavage by the general protein kinase C-dependent shedding machinery, also inhibited HER2 ECD shedding, whereas tissue inhibitor of metalloproteases-2 did not. These data suggest that HER2 cleavage is a process regulated by an as-yet-unidentified distinct protease.
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PMID:Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. 1009 47

The assessment of HER2/neu status is performed to predict monoclonal antibody therapeutic (trastuzumab) responsiveness of invasive breast cancer. The determination is usually performed by immunohistochemistry (IHC), using commercial kits approved by the Food and Drugs Administration (FDA) or by in-house protocols. The authors evaluated HER2 expression using different IHC protocols, to obtain the most concordant results with the FDA-approved system. A tissue microarray paraffin block with 110 samples of several types of histologic specimens was built. On the basis of commercially available kit HercepTest, several protocol steps modifications were made and further compared with HercepTest results. HER2 protein expression was evaluated both semiquantitatively (0, 1+, 2+, 3+ scoring) and qualitatively (specificity and nonspecific background). The most reliable results (98.2% concordance; 0.9% of background) were obtained using a 1:800 primary antibody dilution (Dako-A0485), Tris/EDTA as antigen retrieval solution (Dako-S2367) and a polymer as detection system (EnVision). Tissue microarray controls provided an important contribution, ensuring a rapid and low cost way to standardize and optimize IHC, using in-house protocol, for HER2 expression detection. This in-house protocol for HER2 expression evaluation can be an efficient, specific, and accurate alternative to the FDA-approved kit in a more cost effective manner.
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PMID:HER2/neu detection by immunohistochemistry: optimization of in-house protocols. 1897 84