TPO/c-mpl ligand induces tyrosine phosphorylation of multiple cellular proteins including proto-oncogene products, Vav and c-Cbl, and Ras signaling molecules.

Thrombopoietin (TPO)/c-mpl ligand is a hematopoietic growth factor that stimulates proliferation and maturation of megakaryocytes. To analyze the signaling pathway downstream of the c-mpl product, we used a human megakaryoblastic cell line, Mo7e, that has been proved to be responsive to TPO in terms of DNA synthesis. In this study, we found that TPO treatment resulted in tyrosine phosphorylation of Jak-2 kinase. Moreover, it was revealed that several functional molecules involved in the Ras signaling pathway, Shc and Sos, were phosphorylated by treatment with TPO. Finally, tyrosine phosphorylation of the proto-oncogene products, Vav and c-Cbl, has been proved to be induced by TPO. These results suggest that TPO could activate several signaling pathways including the Jak/Stat pathway, the Ras pathway and possibly another pathway involving the c-Cbl proto-oncogene product.