Document Detail


Ubiquitin-dependent degradation of active Src.
MedLine Citation:
PMID:  10508617     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Signaling by members of the Src family of protein tyrosine kinases, such as Src and Fyn, is important in many biological responses, including gene transcription, cell-cycle progression, and cell adhesion and spreading [1] [2]. Unregulated Src kinase activity has been implicated in the progression of colon cancer and transformation of cultured cells [3] [4] [5] [6]. Thus, precise regulation of Src activity is critical for normal cell growth. Src kinase activity is downregulated by the carboxy-terminal Src kinase (Csk), a tyrosine kinase that phosphorylates a conserved tyrosine residue in the carboxy-terminal tail of Src [7] [8]. When phosphorylated, this tyrosine residue mediates an intramolecular interaction that results in a 'closed' or inactive conformation [1] [2] [9] [10]. Here, we report that loss of csk resulted in a reduction in the abundance of the Src and Fyn proteins, which could be restored by reintroducing catalytically active Csk. The effect of Csk on Src expression was not due to an increase in Src message, but to stabilization of the Src protein. Inhibition of proteasome activity also increased the level of Src protein in csk-deficient cells. Src was found to be ubiquitinated, and activation of Src increased the extent of polyubiquitination. Thus, ubiquitin-proteasome-dependent degradation represents an additional mechanism by which active Src can be downregulated.
Authors:
Y Hakak; G S Martin
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Current biology : CB     Volume:  9     ISSN:  0960-9822     ISO Abbreviation:  Curr. Biol.     Publication Date:  1999 Sep 
Date Detail:
Created Date:  2000-02-14     Completed Date:  2000-02-14     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  9107782     Medline TA:  Curr Biol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1039-42     Citation Subset:  IM    
Affiliation:
Department of Molecular and Cell Biology University of California-Berkeley Berkeley, California 94720-3204, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution
Cell Line
Cysteine Endopeptidases / metabolism*
Enzyme Induction
Humans
Multienzyme Complexes / metabolism*
Mutagenesis, Site-Directed
Phosphorylation
Proteasome Endopeptidase Complex
Protein Conformation
Protein Processing, Post-Translational*
Protein-Tyrosine Kinases
Proto-Oncogene Proteins / genetics,  metabolism
Proto-Oncogene Proteins c-fyn
Proto-Oncogene Proteins pp60(c-src) / chemistry,  genetics,  metabolism
RNA, Messenger / biosynthesis
Signal Transduction / physiology*
Transcription, Genetic
Ubiquitins / physiology*
src-Family Kinases / deficiency,  genetics,  metabolism*,  physiology*
Grant Support
ID/Acronym/Agency:
CA17542/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Multienzyme Complexes; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/Ubiquitins; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.2/CSK tyrosine-protein kinase; EC 2.7.10.2/FYN protein, human; EC 2.7.10.2/Proto-Oncogene Proteins c-fyn; EC 2.7.10.2/Proto-Oncogene Proteins pp60(c-src); EC 2.7.10.2/src-Family Kinases; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.25.1/Proteasome Endopeptidase Complex

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


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