Protein kinase C-epsilon associates with the Raf-1 kinase and induces the production of growth factors that stimulate Raf-1 activity - PubMed (original) (raw)
. 1997 Dec 11;15(24):2921-7.
doi: 10.1038/sj.onc.1201477.
Affiliations
- PMID: 9416835
- DOI: 10.1038/sj.onc.1201477
Protein kinase C-epsilon associates with the Raf-1 kinase and induces the production of growth factors that stimulate Raf-1 activity
M Ueffing et al. Oncogene. 1997.
Abstract
Several observations indicate that the Raf-1 kinase is a downstream effector of protein kinase C-epsilon (PKC epsilon). We recently have shown that Raf-1 is constitutively activated in PKC epsilon transformed Rat6 fibroblasts, and transformation can be reverted by expression of a dominant negative Raf-1, but not a dominant negative Ras mutant (Cacace et al., 1996). Cai et al. (1997) demonstrated that PKC epsilon induced proliferation of NIH3T3 cells is independent of Ras or Src, but depends on Raf-1. These authors further suggested that PKC epsilon activates Raf-1 by direct phosphorylation. Here we have investigated the functional interaction between PKC epsilon and Raf-1. PKC epsilon, but not PKC alpha, was found to bind to the Raf-1 kinase domain. The association appeared to be direct, as it could be reconstituted in vitro with purified proteins. Raf-1 and PKC epsilon could be co-precipitated from Sf-9 insect cells and PKC epsilon transformed NIH313 cells (NIH/epsilon). The association was negatively regulated by ATP in vitro and by TPA treatment in NIH/epsilon cells, but not in Sf-9 insect cells. Raf-1 was constitutively activated in NIH/epsilon cells. However, using coexpression experiments in Sf-9 cells and transiently transfected A293 cells we did not obtain any evidence for a direct activation of Raf-1 by PKC epsilon. PKC epsilon did not induce translocation of Raf-1 to the membrane. Furthermore, PKC epsilon did not activate Raf-1 nor enhance the kinase activity of Raf-1 that had been pre-activated by coexpression of Ras or the Lck tyrosine kinase. In contrast, conditioned media from PKC epsilon transformed cells induced a robust activation of Raf-1. This activation could be partially reproduced by recombinant TGFbeta, a growth factors secreted by PKC epsilon transformed Rat6 cells. In conclusion, our results suggest that PKC epsilon stimulates Raf-1 indirectly by inducing the production of autocrine growth factors.
Similar articles
- PKC epsilon functions as an oncogene by enhancing activation of the Raf kinase.
Cacace AM, Ueffing M, Philipp A, Han EK, Kolch W, Weinstein IB. Cacace AM, et al. Oncogene. 1996 Dec 19;13(12):2517-26. Oncogene. 1996. PMID: 9000126 - Protein kinase C alpha activates RAF-1 by direct phosphorylation.
Kolch W, Heidecker G, Kochs G, Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marmé D, Rapp UR. Kolch W, et al. Nature. 1993 Jul 15;364(6434):249-52. doi: 10.1038/364249a0. Nature. 1993. PMID: 8321321 - Protein kinase Cepsilon is oncogenic in colon epithelial cells by interaction with the ras signal transduction pathway.
Perletti GP, Concari P, Brusaferri S, Marras E, Piccinini F, Tashjian AH Jr. Perletti GP, et al. Oncogene. 1998 Jun 25;16(25):3345-8. doi: 10.1038/sj.onc.1201871. Oncogene. 1998. PMID: 9681835 - The roles of specific isoforms of protein kinase C in growth control and human colon cancer.
Weinstein IB. Weinstein IB. Princess Takamatsu Symp. 1991;22:277-83. Princess Takamatsu Symp. 1991. PMID: 1844247 Review. - The role of protein kinase C in growth control and the concept of carcinogenesis as a progressive disorder in signal transduction.
Weinstein IB. Weinstein IB. Adv Second Messenger Phosphoprotein Res. 1990;24:307-16. Adv Second Messenger Phosphoprotein Res. 1990. PMID: 2119643 Review. No abstract available.
Cited by
- TRPM2 promotes pancreatic cancer by PKC/MAPK pathway.
Lin R, Bao X, Wang H, Zhu S, Liu Z, Chen Q, Ai K, Shi B. Lin R, et al. Cell Death Dis. 2021 Jun 7;12(6):585. doi: 10.1038/s41419-021-03856-9. Cell Death Dis. 2021. PMID: 34099637 Free PMC article. - Activation of protein kinase C and protein kinase D in human natural killer cells: effects of tributyltin, dibutyltin, and tetrabromobisphenol A.
Rana K, Whalen M. Rana K, et al. Toxicol Mech Methods. 2015;25(9):680-8. doi: 10.3109/15376516.2015.1070226. Epub 2015 Jul 31. Toxicol Mech Methods. 2015. PMID: 26228090 Free PMC article. - The Multifunctional Protein Kinase C-ε in Cancer Development and Progression.
Jain K, Basu A. Jain K, et al. Cancers (Basel). 2014 Apr 10;6(2):860-78. doi: 10.3390/cancers6020860. Cancers (Basel). 2014. PMID: 24727247 Free PMC article. - The retinitis pigmentosa GTPase regulator, RPGR, interacts with the delta subunit of rod cyclic GMP phosphodiesterase.
Linari M, Ueffing M, Manson F, Wright A, Meitinger T, Becker J. Linari M, et al. Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1315-20. doi: 10.1073/pnas.96.4.1315. Proc Natl Acad Sci U S A. 1999. PMID: 9990021 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous