JAK2 and JAK1 Constitutively Associate With an Interleukin-5 (IL-5) Receptor α and βc Subunit, Respectively, and Are Activated Upon IL-5 Stimulation

Ogata, Noboru; Kouro, Taku; Yamada, Atsuko; Koike, Masamichi; Hanai, Nobuo; Ishikawa, Takeru; Takatsu, Kiyoshi

doi:10.1182/blood.v91.7.2264.2264_2264_2271

Cited by 21 publications

(31 citation statements)

References 43 publications

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“…4B, bottom panel, and Fig. 5A, third panel from top) [35,36]. Last, the data demonstrate that the molecular signals, which initiate ␤c ubiquitination and proteasome degradation, are early events mediated by JAK kinases and not downstream events mediated by the MAPK, PI-3K, and the p38 MAPK signaling pathways.…”

Section: Role Of Lyn Kinase In ␤C Ubiquitination and Proteasome Degramentioning

confidence: 74%

JAK kinases control IL-5 receptor ubiquitination, degradation, and internalization

Martinez-Moczygemba

Huston

Lei

2007

Journal of Leukocyte Biology

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IL-5, IL-3, and GM-CSF are related hematopoietic cytokines, which regulate the function of myeloid cells and are mediators of the allergic inflammatory response. These cytokines signal through heteromeric receptors containing a specific alpha chain and a shared signaling chain, betac. Previous studies demonstrated that the ubiquitin (Ub) proteasome degradation pathway was involved in signal termination of the betac-sharing receptors. In this study, the upstream molecular events leading to proteasome degradation of the IL-5 receptor (IL-5R) were examined. By using biochemical and flow cytometric methods, we show that JAK kinase activity is required for betac ubiquitination and proteasome degradation but only partially required for IL-5R internalization. Furthermore, we demonstrate the direct ubiquitination of the betac cytoplasmic domain and identify lysine residues 566 and 603 as sites of betac ubiquitination. Lastly, we show that ubiquitination of the betac cytoplasmic domain begins at the plasma membrane, increases after receptor internalization, and is degraded by the proteasome after IL-5R internalization. We propose an updated working model of IL-5R down-regulation, whereby IL-5 ligation of its receptor activates JAK2/1 kinases, resulting in betac tyrosine phosphorylation, ubiquitination, and IL-5R internalization. Once inside the cell, proteasomes degrade the betac cytoplasmic domain, and the truncated receptor complex is terminally degraded in the lysosomes. These data establish a critical role for JAK kinases and the Ub/proteasome degradation pathway in IL-5R down-regulation.

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Section: Role Of Lyn Kinase In ␤C Ubiquitination and Proteasome Degramentioning

confidence: 74%

JAK kinases control IL-5 receptor ubiquitination, degradation, and internalization

Martinez-Moczygemba

Huston

Lei

2007

Journal of Leukocyte Biology

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“…Several distinct signaling cascades are involved in cell proliferation and maturation in the IL-5 receptor-signaling pathway. IL-5 activates a number of kinases, including Bruton-type tyrosine kinase (Btk), Janus kinase (Jak2), Lyn and Raf-1, as well as the phosphatase SHP2 [24][25][26][27][28]. Among these, Btk and Jak2 are essential for proliferation of B-lineage cell lines [24,25].…”

Section: Discussionmentioning

confidence: 99%

Transgene‐mediated hyper‐expression of IL‐5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus

et al. 2004

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IL-5 preferentially activates B1 cells to produce natural antibodies cross-reactive to self antigens. To determine the role of IL-5 in antibody-mediated autoimmune disease, we generated systemic lupus erythematosus (SLE)-prone (NZBÂNZW)F1 mice congenic for IL-5 transgene (TG-F1). The transgene unexpectedly reduced the incidence of lupus nephritis. Anti-DNA antibodies in sera and those produced by splenic B cells in vitro were markedly decreased in TG-F1 mice, while total polyclonal Ig levels were comparable to those in IL-5 transgene-negative (NZBÂNZW)F1 (non-TG-F1) littermates. Flow cytometry-sorted splenic B1 cells showed a significant reduction of anti-DNA antibody synthesis in response to IL-5, while proliferative responses to IL-5 did not significantly differ between TG-F1 and non-TG-F1 mice. As TG-F1 mice aged, frequencies of peripheral B1 cells progressively increased, and the mice frequently developed B cell chronic lymphocytic leukemia (B-CLL). Our results suggest that dysregulated, continuous high expression of IL-5 in SLE-prone mice may directly or indirectly mediate a skewed signaling of proliferation/differentiation of self-antigenactivated B1 cells, leading to suppression of autoimmune disease, but instead to aberrant expansion of B1 cells, giving rise to B-CLL. Thus, this model may provide a clue to the pathogenesis of both SLE and B-CLL.

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“…30 Detailed studies of the truncated cytoplasmic domain of human IL-5Ra revealed that the cytoplasmic stretch at position 346±387, containing the ppvp motif, is necessary for JAK2 binding. 26 Moreover, our deletion analysis revealed that six amino acid residues in the carboxyl-terminal (DC3) region of IL-5Ra appear to be dispensable for IL-5-induced cell proliferation. 29 Thus far, functional analyses of the IL-5Ra have been carried out using in vitro proliferation assays with cultured cell lines altered by conventional gene transfection experiments.…”

Section: Introductionmentioning

confidence: 89%

Functional dissection of the cytoplasmic subregions of the interleukin‐5 receptor α chain in growth and immunoglobulin G1 switch recombination of B cells

Moon¹,

Yoshida²,

Shiiba³

et al. 2001

Immunology

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SUMMARYThe interleukin-5 receptor a chain (IL-5Ra) is known to regulate the development and function of B cells and eosinophils. Although the functions of IL-5Ra cytoplasmic domain subregions have been studied extensively using cultured cell lines, this approach has limitations when studying the functions of distinct primary B-cell subpopulations and their responsiveness to IL-5. In the present study, we generated mice on an IL-5Ra null background, each expressing a mutant form of an IL-5Ra transgene ligated to a m enhancer and VH promoter, either lacking the cytoplasmic DC3 region or substituting two proline residues for alanine (ApvA) in the membrane-proximal ppvp motif of the cytoplasmic domain. The ppvp motif, which mediates activation of JAK2/STAT5 and Btk, also contributes to c-fos, c-jun and c-myc expression. IL-5Ra null mutant mice showed impaired B-1-cell development, reduced serum immunoglobulin G3 (IgG3) and IgM, no IL-5-induced enhancement of B-cell proliferation and IL-5-induced switch recombination from the m gene to c1 gene; these were not recovered following the expression of the ApvA mutant. In contrast, absence of the DC3 region affected the IL-5-induced switch recombination from the m to the c1 gene and B-1-cell development, while IL-5-induced proliferation and IgM production were at levels similar to those of B cells expressing wild-type IL-5Ra transgene. The results clearly indicated that the ppvp motif and the DC3 region of IL-5Ra played distinct roles in B-cell proliferation and differentiation. Thus, this present approach offers new insights into the functions of the cytoplasmic subregions of IL-5Ra, in particular its carboxy-terminal region.

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JAK2 and JAK1 Constitutively Associate With an Interleukin-5 (IL-5) Receptor α and βc Subunit, Respectively, and Are Activated Upon IL-5 Stimulation

Cited by 21 publications

References 43 publications

JAK kinases control IL-5 receptor ubiquitination, degradation, and internalization

JAK kinases control IL-5 receptor ubiquitination, degradation, and internalization

Transgene‐mediated hyper‐expression of IL‐5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus

Functional dissection of the cytoplasmic subregions of the interleukin‐5 receptor α chain in growth and immunoglobulin G1 switch recombination of B cells

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