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Molecular and Cellular Biology, November 2000, p. 8480-8488, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Ras-Dependent Regulation of c-Jun Phosphorylation Is Mediated by the Ral Guanine Nucleotide Exchange Factor-Ral Pathway

Nancy D. de Ruiter,1 Rob M. F. Wolthuis,1,dagger Hans van Dam,2 Boudewijn M. T. Burgering,1 and Johannes L. Bos1,*

Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, 3584 CG Utrecht,1 and Department of Molecular Carcinogenesis, Leiden University Medical Center, 2300 RA Leiden,2 The Netherlands

Received 27 June 2000/Returned for modification 31 July 2000/Accepted 7 August 2000

The transcription factor c-Jun is critically involved in the regulation of proliferation and differentiation as well as cellular transformation induced by oncogenic Ras. The signal transduction pathways that couple Ras activation to c-Jun phosphorylation are still partially elusive. Here we show that an activated version of the Ras effector Rlf, a guanine nucleotide exchange factor (GEF) of the small GTPase Ral, can induce the phosphorylation of serines 63 and 73 of c-Jun. In addition, we show that growth factor-induced, Ras-mediated phosphorylation of c-Jun is abolished by inhibitory mutants of the RalGEF-Ral pathway. These results suggest that the RalGEF-Ral pathway plays a major role in Ras-dependent c-Jun phosphorylation. Ral-dependent regulation of c-Jun phosphorylation includes JNK, a still elusive JNKK, and possibly Src.

* Corresponding author. Mailing address: Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Phone: 31-30-2538977. Fax: 31-30-2539035. E-mail: J.L.Bos{at}med.uu.nl.

dagger Present address: Wellcome/CRC Institute, Cambridge CB2 1QR, United Kingdom.

Molecular and Cellular Biology, November 2000, p. 8480-8488, Vol. 20, No. 22
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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