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Molecular and Cellular Biology, October 1998, p. 5888-5898, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Protein Kinase C-delta Is an Important Signaling Molecule in Insulin-Like Growth Factor I Receptor-Mediated Cell Transformation

Weiqun Li,1,* Yi-Xing Jiang,2 Jiachang Zhang,1 Lilian Soon,1 Lawrence Flechner,1 Veena Kapoor,1 Jacalyn H. Pierce,1 and Lu-Hai Wang2

Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892,1 and Department of Microbiology, The Mount Sinai Medical Center, New York, New York 100292

Received 23 January 1998/Returned for modification 2 March 1998/Accepted 20 July 1998

To investigate the potential role of protein kinase C-delta (PKC-delta ) in insulin-like growth factor I receptor (IGF-IR)-mediated cell transformation, an oncogenic gag-IGF-IR beta -fusion receptor lacking the entire extracellular domain, which was designated NM1, and a full-length IGF-IR were coexpressed with either wild-type PKC-delta (PKC-delta WT) or an ATP-binding mutant of PKC-delta (PKC-delta K376R) in NIH 3T3 fibroblasts. While overexpression of PKC-delta WT did not affect NM1- and IGF-IR-induced focus and colony formation of NIH 3T3 cells, expression of PKC-delta K376R severely impaired these events. In contrast, NM1-mediated cell growth in monolayer was not affected by coexpressing PKC-delta K376R. PKC-delta WT and PKC-delta K376R were constitutively phosphorylated on a tyrosine residue(s) in the NM1- and IGF-IR-expressing cells and were associated with them in an IGF-I-independent manner. Activated IGF-IR was able to phosphorylate purified PKC-delta in vitro and stimulated its kinase activity. Furthermore, the level of endogenous PKC-delta protein was up-regulated through transcriptional activation in response to long-term IGF-IR activation. Taken together, our results demonstrate that PKC-delta plays an important role in IGF-IR-mediated cell transformation, probably via association of the receptor with PKC-delta and its activation through protein up-regulation and tyrosine phosphorylation. Competition with endogenous PKC-delta for NM1 and IGF-IR association by PKC-delta K376R is probably an important mechanism underlying the PKC-delta K376R-mediated inhibition of cell transformation by NM1 and IGF-IR.

* Corresponding author. Mailing address: Laboratory of Cellular and Molecular Biology, Building 37, Room 1E24, NCI, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 496-1347. Fax: (301) 496-8479. E-mail: Liwe{at}dc37a.nci.nih.gov.

Molecular and Cellular Biology, October 1998, p. 5888-5898, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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