Interleukin‐7 activates p56^lck and p59^fyn, two tyrosine kinases associated with the p90 interleukin‐7 receptor in primary human T cells

Abstract

We have investigated signaling events associated with the cloned 90-kDa (p90) interleukin-7 receptor (IL-7R) to determine whether changes in the signaling pathways initiated by this molecule can explain the ability of T cells to proliferate to IL-7 following activation. Using in vitro kinase assays we find that the p90 IL-7R in both unstimulated and activated human T cells is physically associated with two molecules with intrinsic kinase activity. Western blotting analysis reveals these proteins to be the src kinase enzymes, p59fyn and p56lck. Binding of human recombinant IL-7 to the p90 IL-7R results in increased activity of both receptor-associated kinases in both resting and activated mature T cells. Thus, the signaling pathways initiated via the p90 IL-7R-associated src kinases are unlikely to be solely responsible for the proliferation of only activated T cells in response to IL-7. Additional signals, which may derive from other IL-7R-associated molecules such as the gamma c, are clearly required for IL-7-driven proliferation of activated primary T cells.

Murine Pro-B Cells Require IL-7 and Its Receptor Complex to Up-Regulate IL-7Rα, Terminal Deoxynucleotidyltransferase, and cμ Expression

“…Subsequent phosphorylation of tyrosine residues on the cytoplasmic domain of the IL-7R␣ provides docking sites for downstream signaling proteins (65)(66)(67)(68)(69). That these defects do not result simply from the arrested development of Fr.…”

Shared gamma(c) subunit within the human interleukin-7 receptor complex. A molecular basis for the pathogenesis of X-linked severe combined immunodeficiency.

“…Engagement of these subunits by IL-7 leads to the activation of the Janus kinases, JAK1 and JAK3, and the subsequent induction of a signal transducer and activator of transcription (STAT) factor, STAT-5 (7,19,37). Additionally, activation of the src-like kinase family members p56lck, p59fyn, and p53/p56lyn has been reported in various cellular contexts (38)(39)(40). Downstream of the activation of tyrosine kinases is the activation of the insulin receptor substrate-1 (IRS-1) (41) and phosphatidylinositol-3-kinase (42,43).…”

Rapamycin is active against B-precursor leukemiain vitroandin vivo, an effect that is modulated by IL-7-mediated signaling

“…Cytokines play an important role in promoting and controlling normal B cell development (13,14) and are involved in malignant transformation of lymphoid precursor cells (15). One such cytokine is IL-7, an important regulator of T and B cell development.…”