IL-2 Signaling

Interleukin 2 (IL-2) is a growth factor that is important for proliferation and homeostasis of lymphocytes. The IL-2 receptor (IL-2R) contains the following three subunits: the α chain (IL-2R ), which is expressed only on activated lymphocytes; theβ chain (IL-2R ); and the γ common chain (IL-2Rγ c), a subunit shared by several cytokines. The cytoplasmic domains of IL-2R subunits do not possess intrinsic enzymatic activity; rather, IL-2 binding induces oligomerization of IL-2R, which initiates activation of several protein tyrosine kinases (PTKs) and subsequent phosphorylation of the IL-2R complex.The Janus kinases (JAKS) family of PTKs play a central role in IL-2 signaling. JAK3 constitutively binds the cytoplasmic domain of IL-2Rγ c as well as IL-2Rβ , while JAK1 constitutively interacts with IL-2Rβ. JAK3 and JAK1 transphosphorylate and transactivate one another. Other PTKs that associate with the IL-2receptor upon activation are spleen tyrosine kinase (SYK) and lymphocyte protein tyrosine kinase (LCK). While SYK is indirectly activated by JAK3 via JAK1, activation of LCK is independent of JAK3. Though clearly associated with the IL-2 receptor, both LCK and SYK do not play central roles in IL-2 signaling.JAK3 is the primary kinase that is involved in the phosphorylation of signal transducers and activators of transcription (STAT3), leading to dimer formation, nuclear translocation, DNA binding and transactivation of target genes. In addition both JAK3 and JAK1 trigger the mitogen activated protein (MAP) kinase pathway via RAS culminating in the activation of transcription factor- activator protein-1 (AP1).This pathway highlights the key molecular events involved in IL-2 signaling that culminate in the transcriptional activation of genes involved in cell proliferation.