p38MAP Kinase Is a Negative Regulator for ERK1/2-Mediated Growth of AIDS-Associated Kaposi's Sarcoma Cells

doi:10.1006/bbrc.1999.1574

Biochemical and Biophysical Research Communications

Volume 264, Issue 3, 2 November 1999, Pages 676-682

https://doi.org/10.1006/bbrc.1999.1574 Get rights and content

Abstract

AIDS-associated Kaposi's sarcoma (KS) is a cytokine-mediated tumor, at least in the early stages of this disease; however, there is at present no definitive consensus regarding the exact role of intracellular signaling pathways involved in growth of KS cells. We found that KS cell growth factors oncostatin M, sIL-6R/IL-6, TNFα, and IL-1β all activate ERK1/2, and selective blockage of this kinase by PD98059 resulted in a profound inhibition of the cytokine-induced KS cell growth. Concurrently with activation of ERK1/2, these growth factors phosphorylated and activated p38MAPK. The selective inhibition of p38MAPK by SB203580 prominently enhanced the cytokine-induced proliferation of KS cells, thereby indicating that p38MAPK has a negative feedback on mitogenic signals. As these KS cell growth factors lead to simultaneous activation of ERK1/2 and p38MAPK signaling pathways, the concerted effects of these kinase activities may well determine the intensity of cellular proliferative responses to these growth factors.

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We have investigated the molecular mechanisms involved in the activation process of the stress-activated protein kinases (SAPK) p38 and JNK in response to the interleukin-6-type cytokine oncostatin M (OSM). Interestingly, activation of p38 and JNK originates from tyrosine residue 861 in the OSMR; the same tyrosine residue which we identified before to be involved in the activation of the mitogen-activated kinases Erk1/2 [Hermanns, H. M., Radtke, S., Schaper, F., Heinrich, P. C., and Behrmann, I. (2000) J. Biol. Chem. 275, 40742–40748]. Therefore, activation of members belonging to all three MAPK families is mediated by one tyrosine motif in the cytoplasmic region of the human OSMR. Concomitantly, point mutation of this residue abrogates the phosphorylation of these kinases. The Janus kinase Jak1 is absolutely essential for the activation of p38 in response to OSM, while Src kinase family members appear to be generally dispensable. Finally, we demonstrate that mutation of tyrosine 861 abrogates OSMR-mediated cell proliferation and identify Erk1/2 as mainly responsible for the proliferative effect. Erk1/2 activation is negatively influenced by p38 activation and inhibition of p38 significantly prolongs the half-life of OSM-induced Egr-1.
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^☆: Abbreviations used: KS, Kaposi's sarcoma; OM, oncostatin M; sIL-6R, soluble IL-6 receptor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK kinase; HHV-8, human herpesvirus-8

¹: To whom correspondence should be addressed at Department of Pathology I, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

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Regular Articlep38MAP Kinase Is a Negative Regulator for ERK1/2-Mediated Growth of AIDS-Associated Kaposi's Sarcoma Cells☆

Abstract

J. Am. Acad. Dermatol.

Adv. Cancer Res.

Adv. Pharmacol.

Trends Biochem. Sci.

Curr. Opin. Cell Biol.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Cell

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Ann. Intern. Med.

Transplantation

New Engl. J. Med.

New Engl. J. Med.

Curr. Opin. Oncol.

Immunol. Rev.

Science

Science

Science

Regular Article
p38MAP Kinase Is a Negative Regulator for ERK1/2-Mediated Growth of AIDS-Associated Kaposi's Sarcoma Cells☆