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Molecular and Cellular Biology, July 2000, p. 4494-4504, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mapping of Atypical Protein Kinase C within the Nerve Growth Factor Signaling Cascade: Relationship to Differentiation and Survival of PC12 Cells

Marie W. Wooten,* M. Lamar Seibenhener, Kimberly B. W. Neidigh, and Michel L. Vandenplas

Department of Biological Sciences, Program in Cell and Molecular Biosciences, Auburn University, Auburn, Alabama

Received 21 September 1999/Returned for modification 28 October 1999/Accepted 20 March 2000

The pathway by which atypical protein kinase C (aPKC) contributes to nerve growth factor (NGF) signaling is poorly understood. We previously reported that in PC12 cells NGF-induced activation of mitogen-activated protein kinase (MAPK) occurs independently of classical and nonclassical PKC isoforms, whereas aPKC isoforms were shown to be required for NGF-induced differentiation. NGF-induced activation of PKC-iota was observed to be dependent on phosphatidylinositol 3-kinase (PI3K) and led to coassociation of PKC-iota with Ras and Src. Expression of dominant negative mutants of either Src (DN2) or Ras (Asn-17) impaired activation of PKC-iota by NGF. At the level of Raf-1, neither PKC-iota nor PI3 kinase was required for activation; however, PKC-iota could weakly activate MEK. Inhibitors of PKC-iota activity and PI3K had no effect on NGF-induced MAPK or p38 activation but reduced NGF-stimulated c-Jun N-terminal kinase activity. Src, PI3K, and PKC-iota were likewise required for NGF-induced NF-kappa B activation and cell survival, whereas Ras was not required for either survival or NF-kappa B activation but was required for differentiation. IKK existed as a complex with PKC-iota , Src and Ikappa B. Consistent with a role for Src in regulating NF-kappa B activation, an absence of Src activity impaired recruitment of PKC-iota into an IKK complex and markedly impaired NGF-induced translocation of p65/NF-kappa B to the nucleus. These findings reveal that in PC12 cells, aPKCs comprise a molecular switch to regulate differentiation and survival responses coupled downstream to NF-kappa B. On the basis of these findings, Src emerges as a critical upstream regulator of both PKC-iota and the NF-kappa B pathway.

* Corresponding author. Mailing address: Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849. Phone: (334) 844-9245. Fax: (334) 844-9234. E-mail: mwwooten{at}ag.auburn.edu.

Molecular and Cellular Biology, July 2000, p. 4494-4504, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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