The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/12/1947/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 12, December 15, 1997 1947-1955

Article

The Thrombopoietin Receptor Can Mediate Proliferation without Activation of the Jak-STAT Pathway

Marion Dorsch*,{ddagger}, Pang-Dian Fan, Nika N. Danial, Paul B. Rothman§,¶,||, and Stephen P. Goff*,{ddagger},¶

From the * Howard Hughes Medical Institute, {ddagger} Department of Biochemistry and Molecular Biophysics, § Department of Medicine and || Department of Microbiology, and Integrated Program in Molecular, Cellular, and Biophysical Studies, Columbia University, College of Physicians and Surgeons, New York 10032

Cytokine receptors of the hematopoietic receptor superfamily lack intrinsic tyrosine kinase domains for the intracellular transmission of their signals. Instead all members of this family associate with Jak family nonreceptor tyrosine kinases. Upon ligand stimulation of the receptors, Jaks are activated to phosphorylate target substrates. These include STAT (signal transducers and activators of transcription) proteins, which after phosphorylation translocate to the nucleus and modulate gene expression. The exact role of the Jak-STAT pathway in conveying growth and differentiation signals remains unclear. Here we describe a deletion mutant of the thrombopoietin receptor (c-mpl) that has completely lost the capacity to activate Jaks and STATs but retains its ability to induce proliferation. This mutant still mediates TPO-induced phosphorylation of Shc, Vav, mitogen-activated protein kinase (MAPK) and Raf-1 as well as induction of c-fos and c-myc, although at somewhat reduced levels. Furthermore, we show that both wild-type and mutant receptors activate phosphatidylinositol (PI) 3-kinase upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is inhibited in the presence of the PI 3-kinase inhibitor wortmannin. These results demonstrate that the Jak-STAT pathway is dispensable for the generation of mitogenic signals by a cytokine receptor.

Address correspondence to Stephen P. Goff, Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, 701 W 168th Street, HHSC Rm 1127A, New York, NY 10032. Phone: (212) 305-3794; Fax: (212) 305-8692; E-mail: goff{at}cuccfa.ccc.columbia.edu

M. Dorsch is a fellow of the Howard Hughes Medical Institute. S.P. Goff is a Howard Hughes Medical Institute investigator.

1 Abbreviations used in this paper: EMSA, electrophoretic mobility-shift assay; MAPK, mitogen-activated protein kinase; MPLV, myeloproliferative leukemia virus; PI, phosphatidylinositol; STAT, signal transducers and activators of transcription; TPO, thrombopoietin.


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