Document Detail

Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner.
MedLine Citation:
PMID:  11394904     Owner:  NLM     Status:  MEDLINE    
The tyrosine kinase ACK1 phosphorylates and activates the guanine nucleotide exchange factor Dbl, which in turn directs the Rho family GTP-binding proteins. However, the regulatory mechanism of ACK1/Dbl signaling in response to extracellular stimuli remains poorly understood. Here we describe that epidermal growth factor stimulates the ACK1/Dbl pathway, leading to actin cytoskeletal rearrangements. The role of the two ACK1-binding proteins Cdc42 and Grb2 was assessed by overexpression of the Cdc42/Rac interactive binding domain and a dominant-negative Grb2 mutant, respectively. Specific inhibition of the interaction of ACK1 with Cdc42 or Grb2 by the use of these constructs diminished tyrosine phosphorylation of both ACK1 and Dbl in response to EGF. Therefore, the activation of ACK1 and subsequent downstream signaling require both Cdc42-dependent and Grb2-dependent processes within the cell. In addition, we show that EGF transiently induces formation of the focal complex and stress fibers when ACK1 was ectopically expressed. The induction of these structures was totally sensitive to the action of botulinum toxin C from Clostridium botulinum, suggesting a pivotal role of Rho. These results provide evidence that ACK1 acts as a mediator of EGF signals to Rho family GTP-binding proteins through phosphorylation and activation of GEFs such as Dbl.
J Kato-Stankiewicz; S Ueda; T Kataoka; Y Kaziro; T Satoh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  284     ISSN:  0006-291X     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2001 Jun 
Date Detail:
Created Date:  2001-06-07     Completed Date:  2001-07-12     Revised Date:  2011-07-01    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  470-7     Citation Subset:  IM    
Copyright Information:
Copyright 2001 Academic Press.
Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, 226-8501, Japan.
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MeSH Terms
Actins / metabolism
Adaptor Proteins, Signal Transducing*
Botulinum Toxins / pharmacology
Cell Line
Cytoskeleton / metabolism
Epidermal Growth Factor / metabolism*,  pharmacology
GRB2 Adaptor Protein
Guanine Nucleotide Exchange Factors
Hela Cells / cytology,  drug effects,  metabolism
Kidney / cytology,  drug effects,  metabolism
Phosphorylation / drug effects
Protein Binding / drug effects,  physiology
Protein Structure, Tertiary / genetics
Protein-Tyrosine Kinases / metabolism*
Proteins / genetics,  metabolism*
Proto-Oncogene Proteins
Retroviridae Proteins, Oncogenic / metabolism*
Signal Transduction / drug effects,  physiology*
cdc42 GTP-Binding Protein / genetics,  metabolism*
rac1 GTP-Binding Protein / metabolism
rhoA GTP-Binding Protein / metabolism
src Homology Domains / genetics
Reg. No./Substance:
0/Actins; 0/Adaptor Proteins, Signal Transducing; 0/GRB2 Adaptor Protein; 0/GRB2 protein, human; 0/Guanine Nucleotide Exchange Factors; 0/MCF2 protein, human; 0/Proteins; 0/Proto-Oncogene Proteins; 0/Retroviridae Proteins, Oncogenic; 0/botulinum toxin type C; 62229-50-9/Epidermal Growth Factor; EC Kinases; EC protein, human; EC Toxins; EC GTP-Binding Protein; EC GTP-Binding Protein; EC GTP-Binding Protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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