Document Detail

Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation.
MedLine Citation:
PMID:  9271418     Owner:  NLM     Status:  MEDLINE    
A number of cytoplasmic signaling molecules are thought to mediate mitogenic signaling from the activated Neu receptor tyrosine kinase through binding specific phosphotyrosine residues located within the intracellular portion of Neu/c-ErbB-2. An activated neu oncogene containing tyrosine-to-phenylalanine substitutions at each of the known autophosphorylation sites was generated and assessed for its specific transforming potential in Rat1 and NIH 3T3 fibroblasts. Mutation of these sites resulted in a dramatic impairment of the transforming potential of neu. To assess the role of these tyrosine phosphorylation sites in cellular transformation, the transforming potential of a series of mutants in which individual tyrosine residues were restored to this transformation-debilitated neu mutant was evaluated. Reversion of any one of four mutated sites to tyrosine residues restored wild-type transforming activity. While each of these transforming mutants displayed Ras-dependent signaling, the transforming activity of two of these mutants was correlated with their ability to bind either the GRB2 or SHC adapter molecules that couple receptor tyrosine kinases to the Ras signaling pathway. By contrast, restoration of a tyrosine residue located at position 1028 completely suppressed the basal transforming activity of this mutated neu molecule or other transforming neu molecules which possessed single tyrosine residues. These data argue that the transforming potential of activated neu is mediated both by positive and negative regulatory tyrosine phosphorylation sites.
D L Dankort; Z Wang; V Blackmore; M F Moran; W J Muller
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  17     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  1997 Sep 
Date Detail:
Created Date:  1997-09-22     Completed Date:  1997-09-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5410-25     Citation Subset:  IM    
Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario, Canada.
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MeSH Terms
3T3 Cells
Adaptor Proteins, Signal Transducing*
Cell Transformation, Neoplastic
GRB2 Adaptor Protein
Models, Biological
Phenylalanine / metabolism
Proteins / metabolism
Receptor, Epidermal Growth Factor / metabolism
Receptor, erbB-2 / genetics,  metabolism*
Signal Transduction
Tyrosine / metabolism*
ras Proteins / metabolism
src Homology Domains
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/GRB2 Adaptor Protein; 0/Grb2 protein, mouse; 0/Proteins; 55520-40-6/Tyrosine; 63-91-2/Phenylalanine; EC, Epidermal Growth Factor; EC, erbB-2; EC Proteins

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