IL2R signal transduction

Although all three chains of the IL-2R are required for high-affinity binding of IL-2, experiments with chimeric receptor chains containing alternative extracellular domains have demonstrated that ligand-induced heterodimerization of the cytoplasmic domains of the (3 and 7c chains is necessary and sufficient for intracellular signaling. Thus, the role of the a chain appears to be limited to conferring high-affinity binding of IL-2 to the receptor complex. The membrane-proximal cytoplasmic regions of IL-2R(3 and 7c associate noncovalently with the tyrosine kinases JAK1 and JAK3, respectively (Figure 1). IL-2R(3 has been shown to also bind and activate the tyrosine kinases Lck, Fyn and Syk. In T cells, heterodimerization of IL-2R(3 and 7c induces rapid catalytic activation of JAK1 and JAK3 and rapid tyrosine phosphorylation of multiple substrates including JAK1, JAK3, IL-2R3, 7c, the transcription factor STAT5, the adapter molecules SHC and GRB-2, the tyrosine phosphatase SHP-2, the regulatory subunit (p85) of phosphatidylinositol 3-kinase (PI3K), and the MAP

kinase ERK-2 (Figure 1). Signaling results in the induction of multiple target genes associated with proliferation, including c-myc, c-fos, c-jun, and bcl-2, as well as a number of nonmitogenic genes, including IL-2Ra and oncostatin M (osm).

Activation of the tyrosine kinase JAK3 is a critical early event in IL-2 signaling, as disruption of JAK3 catalytic activity abrogates almost all of the above tyrosine phosphorylation events and virtually eliminates the mitogenic response. The few JAK3 kinase-independent events described to date include low-level tyrosine phosphorylation of IL-2R(3 and SHP-2, induction of the proto-oncogene bel-2 and prolongation of cell viability. By contrast, disruption of JAK1 activity is reported to have little effect on mitogenic signaling. The critical role of JAK3 catalytic activity indicates that tyrosine phosphorylation of one or more intracellular substrates is essential for mitogenesis. Indeed, mutation of all cytoplasmic tyrosine residues of IL-2R(3 to phenylalanine eliminates the mitogenic response in the face of normal activation of JAK1 and JAK3. Restoration of either Tyr338, which is required for SHC phosphorylation, or Tyr392 or Tyr510, which can mediate activation of STAT5, rescues the proliferative response in lymphocytes. This suggests that the mitogenic component of the IL-2R signal involves JAK3-dependent tyrosine phosphorylation of IL-2R(3, followed by the recruitment and phosphorylation of SHC, STAT5 or possibly other downstream signaling molecules. Consistent with this model, T cells transformed by the human retrovirus HTLV-I (human T lympho-tropic virus type I) demonstrate a correlation between IL-2-independent growth and constitutive activation of JAK3 and STAT5.

Aside from tyrosine kinases, several other enzymatic activities are associated with IL-2R signaling. Components of the Ras/MAP kinase pathway are activated in response to IL-2, and are thought to regulate the expression of c-fos and c-jun. The lipid kinase PI3K is also activated by IL-2, although the role of this molecule in signaling remains undefined. The IL-2R also induces catalysis of glycosylphos-phatidylinositol through activation of an unidentified enzyme. Finally, the novel protein serine kinase mTOR (mammalian target of rapamycin) has been implicated in IL-2R signaling, as rapamycin, a pharmacological inhibitor of mTOR, greatly reduces IL-2R-mediated proliferative responses. Rapamycin acts in part by delaying the onset of bel-2 expression induced by IL-2 and by preventing the downregul-ation of p27^pJ, an inhibitor of G,- to S-phase progression. Rapamycin is currently being evaluated clinically as an immunosuppressant.

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