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PMID: 7913890 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway.

The EMBO journal ·Vol. 13 ·No. 14 ·1994-07-15 ·Pages 3302-11

Ben-Levy R, Paterson HF, Marshall CJ, Yarden Y

Abstract

The transforming potential of the Neu/ErbB-2 receptor tyrosine kinase undergoes inactivation by deletion of the non-catalytic C-terminal tail, which contains five autophosphorylation sites. To determine which site is essential for oncogenicity, we tailed the C-terminally-deleted mutant with individual autophosphorylation sites. Complete restoration of the transforming action in vitro and in vivo was conferred by a stretch of 12 amino acids that contained the most C-terminal tyrosine autophosphorylation site (Y1253). Reconstitution of transformation was specific to this amino acid sequence because none of the other autophosphorylation sites, when grafted individually, caused transformation, and replacement of the tyrosine with a phenylalanine residue significantly reduced the oncogenic potential of both the full-length and the tailed proteins. When present alone the most C-terminal sequence enabled coupling to a biochemical pathway that includes Ras, MAP kinase and transactivation of Jun. These results indicate that the multiplicity of autophosphorylation sites on a receptor tyrosine kinase is not essential for transformability, and implicate the MAP kinase pathway in transduction of the oncogenic signal of Neu/ErbB-2.

MeSH Terms
Animals Base Sequence Calcium-Calmodulin-Dependent Protein Kinases/metabolism Cell Transformation, Neoplastic/genetics Cells, Cultured DNA Mutational Analysis Enzyme Activation ErbB Receptors/genetics,isolation & purification Fluorescent Antibody Technique Mice Molecular Sequence Data Phosphorylation Protein Processing, Post-Translational Proto-Oncogene Proteins/genetics,isolation & purification Proto-Oncogene Proteins c-jun/metabolism Proto-Oncogene Proteins p21(ras)/metabolism Rats Receptor, ErbB-2 Sequence Deletion Signal Transduction Structure-Activity Relationship
Chemicals
Proto-Oncogene Proteins Proto-Oncogene Proteins c-jun ErbB Receptors Receptor, ErbB-2 Calcium-Calmodulin-Dependent Protein Kinases Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Ben-Levy R
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Paterson H F
Marshall C J
Yarden Y
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1994-07-15
Pages
3302-11
Language
English
Region
England
NLM ID
8208664
PMCID
PMC395227
Subset
IM
Grants
NCI NIH HHS · CA-51712 · United States
External Links
PubMed source PMC Full Text View journal details
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