| Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase C's via a src kinase pathway. | |
MedLine Citation:
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PMID: 11713277 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
Authors:
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M W Wooten; M L Vandenplas; M L Seibenhener; T Geetha; M T Diaz-Meco |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Molecular and cellular biology Volume: 21 ISSN: 0270-7306 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2001 Dec |
Date Detail:
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Created Date: 2001-11-19 Completed Date: 2001-12-21 Revised Date: 2013-04-18 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 8414-27 Citation Subset: IM |
Affiliation:
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Department of Biological Sciences, Auburn University, 331 Funchess Hall, Auburn, AL 36849, USA. mwwooten@acesag.auburn.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Motifs Amino Acid Sequence Animals Cell Differentiation Cell Survival Dose-Response Relationship, Drug Enzyme Activation Genes, Reporter Immunoblotting Models, Biological Molecular Sequence Data Mutagenesis, Site-Directed Mutation NF-kappa B / metabolism Nerve Growth Factor / metabolism* PC12 Cells Phosphorylation Precipitin Tests Proline / chemistry Protein Binding Protein Kinase C / metabolism* Protein Structure, Tertiary Rats Signal Transduction Subcellular Fractions Time Factors Tyrosine / chemistry, metabolism* src-Family Kinases / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/NF-kappa B; 147-85-3/Proline; 55520-40-6/Tyrosine; 9061-61-4/Nerve Growth Factor; EC 2.7.10.2/src-Family Kinases; EC 2.7.11.13/Protein Kinase C |
| Comments/Corrections | |
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