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Novel Regulation of Erythropoietins Raf-1-Mek Signaling Pathway


, : Novel Regulation of Erythropoietins Raf-1-Mek Signaling Pathway. Blood 100(11): Abstract No 2036, November 16

Erythropoietin (Epo) regulates c-myc expression through two distinct pathways: 1) a PI3 kinase dependent pathway that operates on transcriptional initiation at the 5' end of exon 1 and 2) a Raf-1-MAP kinase dependent pathway (also requiring PKC epsilon) that affects the elongation at the 3' end of exon 1 (C. Chen and A.J. Sytkowski. J Biol Chem, 2001.) In studying the Raf-1 pathway further, we have discovered that Epo differentially induces phosphorylation of Raf-1 at serine 338 and phosphorylation at a distinct site within the protein's C-terminal domain, which we have termed "hyperphosphorylation". Deletion of the first N-terminal 160 amino acids of Raf-1, which mediate its interaction with Ras, did not affect Epo-induced phosphorylation of serine 338 or C-terminal hyperphosphorylation, indicating that Ras is not the immediate upstream activator of Raf-1 in this Epo signaling pathway. The Mek inhibitor PD98059 selectively blocked the C-terminal hyperphosphorylation of Raf-1 but did not block Epo induced-phosphorylation of serine 338. Surprisingly, inhibition of Raf-1 hyperphosphorylation by PD98059 also resulted in a marked increase in phosphorylation of Mek. Using an in vitro kinase assay, we found that Mek1 did not phosphorylate Raf-1, but instead phosphorylated a apprx200 kDa Raf-1 associated protein, which we have designated Rap200. The Mek inhibitor PD98059 also blocked the phosphorylation of Rap200. Based upon these results, we propose a model for the regulation of Raf-1-Mek activation in Epo signaling. After stimulation of the Epo receptor, Raf-1 is initially phosphorylated at multiple sites by several kinases, including serine 338 (Pak3), and tyrosines 340 and 341 (Src) resulting in its activation. Activated Raf-1 then phosphorylates Mek1/2, which, in turn, phosphorylates MAP kinases Erk1/2 and Rap200. Phosphorylated Rap200 then directly or indirectly hyperphosphorylates Raf-1 at its C-terminal domain, inactivating its Mek kinase activity or causing it to dissociate from Mek and to translocate elsewhere to interact with one or more new partners. Ras may be one of these new partners. In the presence of Mek inhibitor PD98059, Mek cannot phosphorylate Rap200, preventing the hyperphosphorylation of Raf-1. This active Raf-1 enhances the phosphorylation of Mek. Our results reveal a novel regulatory mechanism for the Raf-1-Mek pathway.

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