Hierarchy of protein tyrosine kinases in interleukin-2 (IL-2) signaling: activation of syk depends on Jak3; however, neither Syk nor Lck is required for IL-2-mediated STAT activation

Mol Cell Biol. 2000 Jun;20(12):4371-80. doi: 10.1128/MCB.20.12.4371-4380.2000.

Abstract

Interleukin-2 (IL-2) activates several different families of tyrosine kinases, but precisely how these kinases interact is not completely understood. We therefore investigated the functional relationships among Jak3, Lck, and Syk in IL-2 signaling. We first observed that in the absence of Jak3, both Lck and Syk had the capacity to phosphorylate Stat3 and Stat5a. However, neither supported IL-2-induced STAT activation, nor did dominant negative alleles of these kinases inhibit. Moreover, pharmacological abrogation of Lck activity did not inhibit IL-2-mediated phosphorylation of Jak3 and Stat5a. Importantly, ligand-dependent Syk activation was dependent on the presence of catalytically active Jak3, whereas Lck activation was not. Interestingly, Syk functioned as a direct substrate of Jak1 but not Jak3. Additionally, Jak3 phosphorylated Jak1, whereas the reverse was not the case. Taken together, our data support a model in which Lck functions in parallel with Jak3, while Syk functions as a downstream element of Jaks in IL-2 signaling. Jak3 may regulate Syk catalytic activity indirectly via Jak1. However, IL-2-mediated Jak3/Stat activation is not dependent on Lck or Syk. While the essential roles of Jak1 and Jak3 in signaling by gammac-utilizing cytokines are clear, it will be important to dissect the exact contributions of Lck and Syk in mediating the effects of IL-2 and related cytokines.

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / physiology*
  • Enzyme Activation
  • Enzyme Precursors / physiology
  • Humans
  • Interleukin-2 / physiology*
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase 3
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / physiology
  • Milk Proteins*
  • Phosphorylation
  • Protein-Tyrosine Kinases / physiology*
  • Receptors, Interleukin-2 / physiology
  • STAT5 Transcription Factor
  • Signal Transduction*
  • Syk Kinase
  • Trans-Activators / physiology*
  • Tumor Suppressor Proteins

Substances

  • DNA-Binding Proteins
  • Enzyme Precursors
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Milk Proteins
  • Receptors, Interleukin-2
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • Trans-Activators
  • Tumor Suppressor Proteins
  • Protein-Tyrosine Kinases
  • JAK3 protein, human
  • Janus Kinase 3
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • SYK protein, human
  • Syk Kinase