Document Detail

Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase C's via a src kinase pathway.
MedLine Citation:
PMID:  11713277     Owner:  NLM     Status:  MEDLINE    
Atypical protein kinase C (PKC) isoforms are required for nerve growth factor (NGF)-initiated differentiation of PC12 cells. In the present study, we report that PKC-iota becomes tyrosine phosphorylated in the membrane coincident with activation posttreatment with nerve growth factor. Tyrosine phosphorylation and activation of PKC-iota were inhibited in a dose-dependent manner by both PP2 and K252a, src and TrkA kinase inhibitors. Purified src was observed to phosphorylate and activate PKC-iota in vitro. In PC12 cells deficient in src kinase activity, both NGF-induced tyrosine phosphorylation and activation of PKC-iota were also diminished. Furthermore, we demonstrate activation of src by NGF along with formation of a signal complex including the TrkA receptor, src, and PKC-iota. Recruitment of PKC-iota into the complex was dependent on the tyrosine phosphorylation state of PKC-iota. The association of src and PKC-iota was constitutive but was enhanced by NGF treatment, with the src homology 3 domain interacting with a PXXP sequence within the regulatory domain of PKC-iota (amino acids 98 to 114). Altogether, these findings support a role for src in regulation of PKC-iota. Tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain. Y256F and Y271F mutations did not alter src-induced activation of PKC-iota, whereas the Y325F mutation significantly reduced src-induced activation of PKC-iota. The functional relevance of these mutations was tested by determining the ability of each mutant to support TRAF6 activation of NF-kappaB, with significant impairment by the Y325F PKC-iota mutant. Moreover, when the Y352F mutant was expressed in PC12 cells, NGF's ability to promote survival in serum-free media was reduced. In summary, we have identified a novel mechanism for NGF-induced activation of atypical PKC involving tyrosine phosphorylation by c-Src.
M W Wooten; M L Vandenplas; M L Seibenhener; T Geetha; M T Diaz-Meco
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  21     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2001 Dec 
Date Detail:
Created Date:  2001-11-19     Completed Date:  2001-12-21     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8414-27     Citation Subset:  IM    
Department of Biological Sciences, Auburn University, 331 Funchess Hall, Auburn, AL 36849, USA.
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MeSH Terms
Amino Acid Motifs
Amino Acid Sequence
Cell Differentiation
Cell Survival
Dose-Response Relationship, Drug
Enzyme Activation
Genes, Reporter
Models, Biological
Molecular Sequence Data
Mutagenesis, Site-Directed
NF-kappa B / metabolism
Nerve Growth Factor / metabolism*
PC12 Cells
Precipitin Tests
Proline / chemistry
Protein Binding
Protein Kinase C / metabolism*
Protein Structure, Tertiary
Signal Transduction
Subcellular Fractions
Time Factors
Tyrosine / chemistry,  metabolism*
src-Family Kinases / metabolism*
Reg. No./Substance:
0/NF-kappa B; 147-85-3/Proline; 55520-40-6/Tyrosine; 9061-61-4/Nerve Growth Factor; EC Kinases; EC Kinase C

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

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