The ErbB-2 oncoprotein contributes to the ability of various adenocarcinomas to metastasize and resist chemotherapy, but the underlying molecular mechanisms are still unknown. Because ErbB-2 belongs to a family of tyrosine kinase receptors, that includes the EGF recpetor (ErbB-1) and two receptors for NDF/heregulin (ErbB-3 and ErbB-4), it is thought that ErbB-2 is activated by a ligand that has so far eluded detection (vertical signaling model). However recent evidence raised the possibility that ErbB-2 functions in tumor cells solely as a ligand-less pan-ErbB signaling subunit of EGF and NDF-receptors (lateral signaling model). Here we propose to contrast these two models by employing a combination of genetic , biochemical and immunological approaches: (1) Genetic- transgenic mice expressing a soluble ErbB-2 fusion protein and animals expressing ErbB-2 mutants that are selectively defective in vertical signaling will presumably reflect the phenotype of the ErbB-2 ligand. (2) Vertical signaling - a conventional soluble ligand will be searched by using a low-background chimera between ErbB-2 (extracellular) and ErbB-1 (intracellular). Membrane-bound ligands will be searched by using soluble versions of ErbB-2 , whereas an antagonist ligand, similar to the Drosophila protein Argos, will be secreened by expression cloning. Phage display peptide libraries will be screened to identify a synthetic analog of the elusive ligand. (3) Lateral signaling - The hierarchy and structural basis of ErbB-2 crosstalk will be identified. Signaling downstream of each heterodimeric receptor combination will be investigated, and an attempt will be made to identify additional ErbB proteins by using expression cloning. (4) signaling inhibition - mAbs to ErbB-2 and its partners, intracellular antibodies, soluble receptors, natural or syntheitic ErbB-2 ligands and synthetic blockers of receptor dimerization will be examined for inhibition of signal transduction and potential therapeutic utility. The proposed research is expected to yield a comprehensive mechanistic understanding of the tumorigenic action of ErbB proteins and also identify new molecules, such as natural or synthetic ligands, soluble receptors and specific antibodies, that may have prognostic and therapeutic values.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA072981-01
Application #
2011033
Study Section
Pathology B Study Section (PTHB)
Project Start
1997-04-25
Project End
2000-03-31
Budget Start
1997-04-25
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Weizmann Institute of Science
Department
Type
DUNS #
City
Rehovot
State
Country
Israel
Zip Code
76100
Schneider, Marlon R; Yarden, Yosef (2014) Structure and function of epigen, the last EGFR ligand. Semin Cell Dev Biol 28:57-61
Lauriola, Mattia; Enuka, Yehoshua; Zeisel, Amit et al. (2014) Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment. Nat Commun 5:5073
Maron, Ruth; Schechter, Bilha; Mancini, Maicol et al. (2013) Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2. Proc Natl Acad Sci U S A 110:15389-94
Mahlknecht, Georg; Maron, Ruth; Mancini, Maicol et al. (2013) Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth. Proc Natl Acad Sci U S A 110:8170-5
Ferraro, Daniela A; Gaborit, Nadège; Maron, Ruth et al. (2013) Inhibition of triple-negative breast cancer models by combinations of antibodies to EGFR. Proc Natl Acad Sci U S A 110:1815-20
Pradeep, C-R; Kostler, W J; Lauriola, M et al. (2012) Modeling ductal carcinoma in situ: a HER2-Notch3 collaboration enables luminal filling. Oncogene 31:907-17
Tarcic, Gabi; Avraham, Roi; Pines, Gur et al. (2012) EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF. FASEB J 26:1582-92
Lindzen, M; Carvalho, S; Starr, A et al. (2012) A recombinant decoy comprising EGFR and ErbB-4 inhibits tumor growth and metastasis. Oncogene 31:3505-15
Avraham, Roi; Yarden, Yosef (2012) Regulation of signalling by microRNAs. Biochem Soc Trans 40:26-30
Bossel Ben-Moshe, Noa; Avraham, Roi; Kedmi, Merav et al. (2012) Context-specific microRNA analysis: identification of functional microRNAs and their mRNA targets. Nucleic Acids Res 40:10614-27

Showing the most recent 10 out of 59 publications