THE THROMBOPOIETIN RECEPTOR CAN MEDIATE PROLIFERATION WITHOUT ACTIVATION OF THE JAK-STAT PATHWAY

Cytokine receptors of the hematopoietic receptor superfamily lack intr insic tyrosine kinase domains for the intracellular transmission of th eir signals. Instead all members of this family associate with Jak fam ily nonreceptor tyrosine kinases. Upon ligand stimulation of the recep tors, Jaks are activated to phosphorylate target substrates. These inc lude STAT (signal transducers and activators of transcription) protein s, 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 che thrombopoietin receptor (c-mpl) that has compl etely lost the capacity to activate Jaks and STATs but retains its abi lity to induce proliferation. This mutant still mediates TPO-induced p hosphorylation of Shc, Vav, mitogen-activated protein kinase (MAPK) an d Raf-1 as well as induction of c-fos and c-myc, although at somewhat reduced levels. Furthermore, we show that both wildtype and mutant rec eptors activate phosphatidylinositol (PI) 3-kinase upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is inhibite d in the presence of the PI 3-kinase inhibitor wortmannin. These resul ts demonstrate that the Jak-STAT pathway is dispensable for the genera tion of mitogenic signals by a cytokine receptor.