Receptor expression is essential for proliferation induced by dimerized Jak kinases.

Two members of Jak kinases, Jak1 and Jak3, are associated with the cytoplasmic domains of the interleukin-2 (IL-2) receptor (IL-2R) beta chain (IL-2Rbeta) and the common cytokine receptor gamma chain (gammac), respectively, and accumulating evidence indicates their functional importance in IL-2 signaling. Here, I showed that coumermycin-induced chemical heterodimerization of Jak1 and Jak3 but not homodimerization of Jak1 or Jak3 induces cell proliferation of an IL-2R-reconstituted cell line. In this regard, expression of IL-2Rbeta was essential for cell proliferation by chemical heterodimerization of Jak1 and Jak3, indicating that dimerized Jak1 and Jak3 induce heterodimerization of IL-2Rbeta and gammac, which may activate receptor-bound signaling molecules. Previous reports using chemical dimerization suggest that dimerization of Jak kinases is sufficient to induce cell proliferation. The present study indicates that re-evaluation of this conclusion is necessary and that interpretation of functional analysis of signaling molecules using chemical dimerizers needs more careful assessment.