Fig. 3.

The TAK1-PIM2 pathway in the mutual interaction between MM cells and the bone microenvironment. PIM2 is a novel pro-survival mediator for MM cells. Interaction with the MM bone marrow microenvironment potentiates PIM2 expression in MM cells through activation of the JAK2/STAT3 pathway by IL-6 and the NF-κB pathway by TNF family cytokines, TNF-α, BAFF, and APRIL, to promote MM cell growth and survival. At the same time, PIM2 is induced in osteoclasts and bone marrow stromal cells (BMSCs) though the interaction with MM cells to cause bone destruction. TAK1 is overexpressed and activated upstream of PIM2 in MM cells, BMSCs and osteoclasts through mutual interaction between these cells in the bone marrow. Besides PIM2 upregulation, TAK1 mediates a wide range of intracellular signaling pathways, including VEGF production via ERK in MM cells and the expression of VCAM-1 and RANKL in BMSCs. Therefore, TAK1 activation is vital for MM cell growth and survival and bone destruction