Document Detail

SH2-B is a positive regulator of nerve growth factor-mediated activation of the Akt/Forkhead pathway in PC12 cells.
MedLine Citation:
PMID:  14565960     Owner:  NLM     Status:  MEDLINE    
To gain insight into the mechanism by which the adapter protein SH2-B promotes nerve growth factor (NGF)-mediated neuronal differentiation and survival, the effect of SH2-B on the serine/threonine kinase Akt/protein kinase B and downstream effector proteins was examined. PC12 cells stably overexpressing SH2-Bbeta, which exhibit enhanced NGF-induced neuronal differentiation compared with control cells, showed enhanced and prolonged NGF-induced phosphorylation of Akt on Ser473 and Akt enzymatic activity. Surprisingly, NGF-induced phosphorylation of Akt on Ser473 and Akt activity were not altered in cells overexpressing SH2-Bbeta(R555E) with a defective SH2 domain, despite the ability of the overexpressed SH2-Bbeta(R555E) to block NGF-induced differentiation. Consistent with SH2-Bbeta enhancing the activity of Akt, cells overexpressing SH2-Bbeta but not SH2-Bbeta(R555E) exhibited increased and/or prolonged phosphorylation of the pro-apoptotic Akt effector proteins, glycogen synthase kinase-3, and forkhead transcription factors, FKHRL1/FOXO3 and FKHR/FOXO1. Immunolocalization studies indicated that, although ectopically expressed FKHR was primarily concentrated in the cytoplasm of control cells and cells transiently overexpressing SH2-Bbeta, it was concentrated in the nucleus of cells transiently overexpressing SH2-Bbeta(R555E). Similarly, SH2-Bbeta stimulated the accumulation of FKHR in the cytoplasm of 293T and COS-7 cells, whereas SH2-Bbeta(R555E) enhanced its accumulation in the nucleus. In PC12 cells stably expressing forms of SH2-Bbeta, SH2-Bbeta mimicked the ability of NGF to promote redistribution of FKHR to the cytoplasm whereas SH2-Bbeta(R555E) blocked this effect of NGF. Taken together, these data indicate that SH2-B is a positive regulator of NGF-mediated activation of the Akt/Forkhead pathway.
Xiaohong Wang; Linyi Chen; Travis J Maures; James Herrington; Christin Carter-Su
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2003-10-16
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  279     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2003-12-25     Completed Date:  2004-03-03     Revised Date:  2014-07-16    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  133-41     Citation Subset:  IM    
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MeSH Terms
Adaptor Proteins, Signal Transducing
Amino Acid Substitution
Carrier Proteins / genetics,  physiology*
Cell Differentiation / drug effects
Cell Line
DNA Primers
Forkhead Transcription Factors
Mutagenesis, Site-Directed
Nerve Growth Factor / pharmacology*
Nuclear Proteins / metabolism*
PC12 Cells
Phosphoserine / metabolism
Protein Isoforms / metabolism
Protein-Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-akt
Recombinant Fusion Proteins / metabolism
Recombinant Proteins / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects
Transcription Factors / metabolism*
src Homology Domains
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Carrier Proteins; 0/DNA Primers; 0/Forkhead Transcription Factors; 0/Nuclear Proteins; 0/Protein Isoforms; 0/Proto-Oncogene Proteins; 0/Recombinant Fusion Proteins; 0/Recombinant Proteins; 0/SH2B1 protein, human; 0/Sh2bpsm1 protein, rat; 0/Transcription Factors; 17885-08-4/Phosphoserine; 9061-61-4/Nerve Growth Factor; EC protein, human; EC protein, rat; EC Kinases; EC Proteins c-akt

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