IL-6 mediated activation of STAT3 bypasses Janus kinases in terminally differentiated B lineage cells

Abstract

Cytokine signaling generally occurs through receptors lacking tyrosine kinase activity. Aggregation of receptors leads to activation of receptor associated Janus kinases (Jaks) which in turn phosphorylate members of a family of transcription factors (STATs) that translocate to the nucleus and regulate gene expression. In the case of Interleukin-6 (IL-6), the consensus for signaling in B lineage cells has been that Jak1, Jak2 and Tyk2 are all phosphorylated upon ligand binding and participate in activation of downstream elements, in particular STAT3. In other cell types, Jak1 has been demonstrated to be absolutely required for IL-6 mediated activation of STAT3. In the present studies, we have identified a series of end stage B cell (plasma cell) lines that fail to express Jak1, but phosphorylate STAT3 in response to IL-6. No evidence was found for a requirement of other Jak family members in the activation of STAT3. STAT3 tyrosine phosphorylation was inhibited in a dose dependent manner by the MEK inhibitor U0126, but not by inhibitors of PI-3K or Src kinases. Moreover, STAT3 phosphorylation was similarly inhibited in lines expressing Jak1 wherein Jak1 was phosphorylated upon IL-6 stimulation and Jak1 phosphorylation was not inhibited by U0126. These results indicate that the MAPK pathway plays a critical role in IL-6 mediated tyrosine phosphorylation of STAT3 and suggests that Jak kinases may not be required in this cascade. Thus, it may be important to re-evaluate the role of Jak kinases in other cytokine signaling pathways as well.

Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells

“…This result is consistent with the work of others who demonstrated that signal transduction through IL-6 activates Src family kinases, most notably Hck kinases (Hallek et al, 1997;Schaeffer et al, 2001). A more recent report has demonstrated that IL-6 activation of Stat3 did not require JAK activity but instead was inhibited by inhibitors of MAPK pathway (Kopantzev et al, 2002). In addition, in myeloid cells, IL-3 induces STATs through Src-kinases rather than JAKs (Chaturvedi et al, 1998).…”

Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

“…On the basis of studies performed in other cell lines, diverse mechanisms could be considered for explanation of lack of phosphorylation of STAT3. In a number of plasma cell lines, STAT3 phosphorylation in response to IL-6 was detected although Jak1 protein is not expressed (Kopantzev et al 2002). Those authors also demonstrated that IL-6 may fail to induce phosphorylation of Jak2 in plasma cells.…”

Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells

“…Several other kinases have been implicated in the phosphorylation of STAT3, including members of the Src family (hck, src), Erb2, anaplastic lymphoma kinase, protein kinase C-␦, c-fes, and epidermal growth factor receptor (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). Whether any of these kinases are active in MM cells, and which of these kinases is activated by IL-6, is not fully known.…”