Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.2.3.23 (GAS)
 957 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-5 (IL-5) drives the terminal differentiation of myeloid progenitors to the eosinophil lineage; blocks eosinophil apoptosis; and primes eosinophils for enhanced functional activities in allergic, parasitic, and other eosinophil-associated diseases. Here we describe a novel signaling pathway activated by the IL-5 receptor in eosinophils involving the CrkL adapter protein. We determined whether IL-5 induces activation of CrkL and STAT5 in eosinophils using both the human eosinophil-differentiated AML14.3D10 cell line and purified peripheral blood eosinophils from normal donors. Stimulation of AML14.3D10 cells or blood eosinophils with IL-5 induced rapid tyrosine phosphorylation of the CrkL adapter and STAT5 and the association of CrkL and STAT5 in vivo as evidenced by the detection of STAT5 in anti-CrkL immunoprecipitates. The resulting CrkL.STAT5 complexes translocated to the nucleus and bound STAT5 consensus DNA-binding sites present in the promoters of IL-5-regulated genes, as shown in gel mobility and antibody supershift assays. IL-5 also induced marked activity of an 8X-GAS (interferon gamma-activated site)-luciferase reporter construct in transient transfections of AML14.3D10 eosinophils, demonstrating that these complexes play a functional role in IL-5 signaling. CrkL was also found to interact, via its N-terminal SH3 domain, with C3G, a guanine exchange factor for the small G-protein Rap1, which was also rapidly activated in an IL-5-dependent manner in these cells, establishing that CrkL mediates downstream activation of at least two signaling cascades in IL-5-stimulated eosinophils. Thus, the CrkL adapter plays an important role in IL-5 signaling in the eosinophil, acting as a nuclear adapter for STAT5 and as an upstream regulator of the C3G-Rap1 signaling pathway.
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PMID:Engagement of the CrkL adapter in interleukin-5 signaling in eosinophils. 1092 30

We sought to determine the functional role of the CrkL adapter protein and downstream pathways in interferon signaling. In experiments using CrkL(--) mouse embryonic fibroblasts, we found that CrkL is required for IFN alpha-dependent gene transcription via GAS elements, apparently via the formation of DNA-binding complexes with Stat5. On the other hand, gene transcription via ISRE elements is intact in the absence of CrkL, indicating that the regulatory effects on gene transcription are mediated only via the formation of CrkL:Stat5 complexes. Our studies also indicate that activation of the small GTPase Rap1 by IFN alpha is defective in cells lacking CrkL, indicating that the protein plays a critical role in regulating activation of the growth inhibitory C3G/Rap1 pathway. The IFN alpha-inducible activation of the small GTPase Rap1 requires a functional N-terminus SH3 domain in the CrkL protein, while the C-terminus SH3 domain does not appear to play a role in such a CrkL-function. We also demonstrate that both the Tyk-2 and Jak-1 kinases are required for activation of the CrkL/Rap1 pathway, as the Type I IFN-dependent GTP-bound form of Rap1 is inhibited by overexpression of dominant-negative Tyk-2 or Jak-1 mutants and is defective in cells lacking Tyk-2 or Jak-1. Taken altogether, these findings indicate that CrkL provides an important link between Jak-kinases and downstream cascades that play critical roles in IFN-dependent transcriptional regulation and induction of growth inhibitory responses.
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PMID:The CrkL adapter protein is required for type I interferon-dependent gene transcription and activation of the small G-protein Rap1. 1186 27