The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop

Yasukawa, Hideo; Misawa, Hiroyuki; Sakamoto, Hiroshi; Masuhara, Masaaki; Sasaki, Atsuo T.; Wakioka, Toru; Ohtsuka, Satoshi; Imaizumi, Tsutomu; Matsuda, Tadashi; Ihle, James N.; Yoshimura, Akihiko

doi:10.1093/emboj/18.5.1309

Cited by 657 publications

(656 citation statements)

References 41 publications

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“…4C). This is in agreement with the established inhibitory mechanism of SOCS-1 through direct binding to the kinases of the Janus family (23,24,53) and emphasizes the difference in the inhibitory mechanisms of SOCS-1 and SOCS-3.…”

Section: Discussionsupporting

confidence: 91%

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

Hörtner

Nielsch

Mayr

et al. 2002

The Journal of Immunology

122

101

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G-CSF is a polypeptide growth factor used in treatment following chemotherapy. G-CSF regulates granulopoiesis and acts on its target cells by inducing homodimerization of the G-CSFR, thereby activating intracellular signaling cascades. The G-CSFR encompasses four tyrosine motifs on its cytoplasmic tail that have been shown to recruit a number of regulatory proteins. Suppressor of cytokine signaling 3 (SOCS-3), also referred to as cytokine-inducible Src homolgy 2-containing protein 3, is a member of a recently discovered family of feedback inhibitors that have been shown to inhibit the Janus kinase/STAT pathway. In this study, we demonstrate that human SOCS-3 is rapidly induced by G-CSF in polymorphonuclear neutrophils as well as in the myeloid precursor cell line U937 and that SOCS-3 negatively regulates G-CSFR-mediated STAT activation. Most importantly, we show that SOCS-3 is recruited to the G-CSFR in a phosphorylation-dependent manner and we identify phosphotyrosine (pY)729 as the major recruitment site for SOCS-3. Furthermore, we demonstrate that SOCS-3 directly binds to this pY motif. Surface plasmon resonance analysis reveals a dissociation constant (KD) for this interaction of around 2.8 μM. These findings strongly suggest that the recruitment of SOCS-3 to pY729 is important for the modulation of G-CSFR-mediated signal transduction by SOCS-3.

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Section: Discussionsupporting

confidence: 91%

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

Hörtner

Nielsch

Mayr

et al. 2002

The Journal of Immunology

122

101

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“…Indeed, TEL-JAK2 transformed Ba/F3 cells expressing SOCS-1 died within 48 h as seen by staining with the vital dye 7-AAD and AnnexinV (Figure 2c). SOCS-1 binds to JAK2 through its SH2 domain and a peptide sequence that includes the phosphorylated Y1007 residue in the activation loop of JAK2 catalytic domain (Yasukawa et al, 1999). A point mutation at residue R105 in the SOCS-1 SH2 domain has been shown to impair SOCS-1 mediated inhibition of JAK kinases .…”

Section: Socs-1 Inhibits the Proliferation Of Cells Transformed By Onmentioning

confidence: 99%

“…SOCS-1 binds directly to the conserved regulatory tyrosine in the activation loop of the JAK2 kinase (JH1) domain through its SH2 domain and inhibits JAK kinase activity presumably through occlusion of the substrate binding site Yasukawa et al, 1999). SOCS-1 also interferes with signaling through the KIT receptor tyrosine kinase, though in a manner which does not suppress its catalytic activity (De Sepulveda et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

The tumor suppressor activity of SOCS-1

et al. 2002

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SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 de®cient mice die within the ®rst three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 7/7 ®broblasts are more sensitive than wild type ®broblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.

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“…It has been reported that SOCS suppress cytokine signal transduction by binding to phosphorylated tyrosine residues on cytokine receptor chains and the receptor-associated tyrosine phosphorylated Jaks via the SH2 domain. The binding results in switching off Jaks by acting pseudosubstrates and recruiting ubiquitination machinery via the SOCS-box domain (Yasukawa et al, 1999). SOCS1 is induced by various cytokines including interferon (IFN)-g, interleukin-4, TNF-a, as well as growth hormones, and downregulates the signals induced by these cytokines in a feedback loop.…”

Section: Introductionmentioning

confidence: 99%

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

Hur

2009

Oncogene

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Suppressors of cytokine signaling (SOCS) are negative regulators of cytokine-induced signal transduction, which play multiple roles in cell growth, differentiation and apoptosis. In this study, the regulatory role of SOCS in oxidative stress-induced apoptosis was investigated. In Jurkat T cells and mouse splenocytes, we have found that SOCS1 is induced in response to tumor necrosis factor-a or H 2 O 2 , concomitant with the activation of Jaks which act as important mediators of reactive oxygen species (ROS)-induced apoptosis upstream of p38 mitogenactivated protein kinase. Using SOCS1 overexpressing or knockdown Jurkat T-cell systems we clearly demonstrate that, SOCS1 inhibits the ROS-mediated apoptosis. The antiapoptotic action of SOCS1 was exerted not only by suppressing Jaks, but also by sustaining protein tyrosine phosphatase (PTP) activities. Notably, SOCS1-transduced cells displayed increase in thioredoxin levels and decrease in ROS generation induced by oxidative stress. In addition, the Jak-inhibiting and PTP-sustaining effect of SOCS1 was significantly reduced on thioredoxin ablation. Moreover, coimmunoprecipitation data revealed molecular interaction of SHP1 or CD45 with thioredoxin, which was promoted in SOCS1-transfected cells. Together, our data strongly suggest that both the protection of PTPs by thioredoxin from ROS attack and the attenuation of Jaks account for the antiapoptotic function of SOCS1 in immune cells under oxidative stress.

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The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop

Cited by 657 publications

References 41 publications

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

Suppressor of Cytokine Signaling-3 Is Recruited to the Activated Granulocyte-Colony Stimulating Factor Receptor and Modulates its Signal Transduction

The tumor suppressor activity of SOCS-1

SOCS1 protects protein tyrosine phosphatases by thioredoxin upregulation and attenuates Jaks to suppress ROS-mediated apoptosis

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