Functional Cooperation of the Interleukin-2 Receptor β Chain and Jak1 in Phosphatidylinositol 3-Kinase Recruitment and Phosphorylation

ABSTRACT

Phosphatidylinositol 3-kinase (PI 3-K) plays an important role in signaling via a wide range of receptors such as those for antigen, growth factors, and a number of cytokines, including interleukin-2 (IL-2). PI 3-K has been implicated in both IL-2-induced proliferation and prevention of apoptosis. A number of potential mechanisms for the recruitment of PI 3-K to the IL-2 receptor have been proposed. We now have found that tyrosine residues in the IL-2 receptor β chain (IL-2Rβ) are unexpectedly not required for the recruitment of the p85 component of PI 3-K. Instead, we find that Jak1, which associates with membrane-proximal regions of the IL-2Rβ cytoplasmic domain, is essential for efficient IL-2Rβ–p85 interaction, although some IL-2Rβ–p85 association can be seen in the absence of Jak1. We also found that Jak1 interacts with p85 in the absence of IL-2Rβ and that IL-2Rβ and Jak1 cooperate for the efficient recruitment and tyrosine phosphorylation of p85. This is the first report of a PI 3-K–Jak1 interaction, and it implicates Jak1 in an essential IL-2 signaling pathway distinct from the activation of STAT proteins.

ACKNOWLEDGMENTS

We thank D. A. Cantrell for providing the PI 3-K p85 DNA (3), J. J. O’Shea for the human Jak3 cDNA, J. Hakimi for the hMikβ1 antibody, M. Tsang and R & D Systems for the anti-IL-2Rβ antiserum, K. Sugamura for Molt4β cells, I. Miyoshi for MT-2 cells, J. Yodoi for YT cells, J. Ihle for the murine Jak1 cDNA in pMLCMV, J. Ashwell for the Lck cDNA, and T. Mustelin for the multiple PI 3-K p85 truncation mutations. We thank J. H. Pierce, J. Ashwell, L. E. Samelson, A. Morimoto, and L. C. Cantley for valuable discussions and/or critical comments, and we thank A. Puel and S. John for assistance with preparing figures.