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Crosstalk between the Smad and the Mitogen-Activated Protein Kinase Pathways is Essential for Erythroid Differentiation of Erythroleukemia Cells Induced by TGF-β, Activin, Hydroxyurea and Butyrate

Salem Akel, Daniel Bertolette and Francis W Ruscetti

The role of crosstalk between the Smad and the MAPK signaling pathways in activin-, transforming growth factor- β (TGF-β)-, hydroxyurea (HU) - and butyrate-dependent erythroid differentiation of K562 leukemic cells was studied. Treatment with all four inducers caused transient phosphorylation of Smad2/3 and MAPK proteins including ERK, p38 and JNK. Use of specific inhibitors of p38, ERK and JNK MAPK proteins, and TGF-β type I receptor indicated that differentiation induced by each of these agents involves activation of Smad2/3 and p38 MAPK, and inhibition of ERK MAPK. Also, treatment of cells with an inhibitor of protein serine/threonine phosphatase, okadaic acid (OA), induced phosphorylation of Smad2/3, and p38 MAPK, coincident with its induction of erythroid differentiation. Specific inhibition of TGF-β type I receptor kinase activity not only abolished TGF-β/activin effects but also prevented Smad2/3 activation and erythroid differentiation induced by OA, HU and butyrate. The TGF-β type I receptor kinase inhibitor blocked OA-induced differentiation but not p38 MAPK phosphorylation demonstrating that signals from both pathways are needed. As previously observed, addition of ERK1/2 MAPK inhibitors upregulated Smad2/3 phosphorylation and enhanced differentiation, but these effects were dependent on signals from the TGF-β type I receptor. These data indicate that activation of both Smad2/3 and p38 MAPK signaling pathways is a prerequisite to induce erythroid differentiation of erythroleukemia cells by activin, TGF-β, HU, OA and butyrate