Differential Substrate Recognition Capabilities of Janus Family Protein Tyrosine Kinases Within the Interleukin 2 Receptor (I12R) System: Jak3 as a Potential Molecular Target for Treatment of Leukemias with a Hyperactive Jak-Stat Signaling Machinery

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Abstract
Substrate recognition by Janus family protein tyrosine kinases was examined utilizing recombinant baculovirus produced components of the interleukin 2 receptor (IL2R) system i.e. Jakl, Transducers and Activators of Transcription (STAT). Wild type Jak3 was able to tyrosine phosphorylate a kinase-dead Jak1 (Jak1E908). In contrast wild type Jak1 was unable to tyrosine phosphorylate kinase dead Jak3 (Jak3E851). This unilateral transphosphorylation between Jak3 and Jak1 prompts the hypothesis that in the IL2R system the activation of Jak3 precedes Jak1 activation. Both the IL2Rβ and IL2Rγc subunits underwent tyrosine phosphorylation when co-expressed with wild-type Jak3. By comparison only IL2Rβ was recognized and tyrosine phosphorylated by wild-type Jak1. These results are consistent with the notion that Jak1 is pre-associated with IL2Rβ and Jak3 is pre-associated with IL2Rγc. STAT1, STAT3, and STAT5 underwent tyrosine phosphorylation when co-expressed with Jak1 and therefore are substrates for the respective Jak kinases. In contrast, Jak3 co-expression resulted in tyrosine phosphorylation of STAT3 and STAT5 but not STAT1. Notably a polypeptide representing the kinase domain of Jak 3(Jak3-JH1) gained the ability to tyrosine phosphorylate STAT1, suggesting that the changes in substrate recognition may be influenced by domains outside the kinase domain. These findings provide evidence that Jak1 and Jak3 differentially recognize specific substrates, thereby having the ability to contribute specific signals, and the substrate specificity may be influenced by multiple domains of these tyrosine kinases.

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