Cytokine‐inducible SH2 protein‐3 (CIS3/SOCS3) inhibits <i>Janus</i> tyrosine kinase by binding through the N‐terminal kinase inhibitory region as well as SH2 domain

Sasaki, Atsuo T.; Yasukawa, Hideo; Suzuki, Asuka; Kamizono, Shintaro; Syoda, Takanori; Kinjyo, Ichiko; Sasaki, Mika; Johnston, James A.; Yoshimura, Akihiko

doi:10.1046/j.1365-2443.1999.00263.x

Cited by 354 publications

(354 citation statements)

References 30 publications

(52 reference statements)

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“…Thus, the specific pattern of the observed inhibition strongly suggests that Jak2-V617F is still sensitive to SOCS3-mediated inhibition. This also shows that the inhibitory mechanism is identical for Jak2-WT and Jak2-V617F, and corresponds to the mechanism extensively characterized by Sasaki et al (1999). Finally, using an siRNA approach, we found that both SOCS1 and SOCS3 can regulate Jak2-V617F expression levels ( Figure 6).…”

Section: Regulation Of Mutant Jak2 By Socs Proteinssupporting

confidence: 73%

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

et al. 2009

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Section: Regulation Of Mutant Jak2 By Socs Proteinssupporting

confidence: 73%

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

et al. 2009

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“…SOCS proteins are known to inhibit JAK activity by binding to JAK-proximal sites on cytokine receptors, which subsequently block access of STATs to a receptor-binding site on JAKs. 2,29 STAT3 is a transcription factor with oncogenic potential. There is growing evidence showing that STAT3 may play an important role in the pathogenesis of ALK þ ALCL, and that ALK and JAK3 contribute to STAT3 activation.…”

Section: Discussionmentioning

confidence: 99%

Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma

et al. 2004

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Using a cDNA microarray, we found that suppressor of cytokine signaling 3 (SOCS3) is highly expressed in anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) cell lines. As SOCS3 is induced by activated signal transducer and activator of transcription 3 (STAT3), and ALK activates STAT3, we hypothesized that SOCS3 may play a role in ALK + ALCL pathogenesis via the Janus kinase 3 (JAK3)-STAT3 pathway. Using ALCL cell lines, we show by coimmunoprecipitation experiments that SOCS3 physically binds with JAK3 in vitro, and that JAK3 inhibition by WHI-P154 downregulates SOCS3 expression. Western blot analysis confirmed expression of SOCS3 and also showed coexpression of phosphorylated (activated) STAT3 (pSTAT3). Direct sequencing of the SOCS3 gene showed no mutations or alternative splicing. In ALCL tumors that were assessed by immunohistochemistry, nine of 12 (75%) ALK + tumors were SOCS3 positive and eight (67%) coexpressed pSTAT3. In comparison, 18 of 25 (72%) ALKtumors were SOCS3 positive and seven (28%) coexpressed pSTAT3. These results show that SOCS3 is overexpressed in ALCL, attributable to JAK3-STAT3 activation and likely related to ALK in ALK + tumors. However, SOCS3 is also expressed in tumors that lack STAT3 and ALK suggesting alternative mechanisms of upregulation.

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“…SOCS1 inhibits JAK kinase activation (Sakamoto et al, 1998), while SOCS3 inhibits JAK2 activity (Sasaki et al, 1999). Conse- Fig.…”

Section: Discussionmentioning

confidence: 99%

Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A₂, cyclooxygenase, and lipoxygenase

Yang

Jou

et al. 2004

Glia

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Previously we have reported that thrombin induces inflammatory mediators in brain glial cells (Ryu et al. 2000. J Biol Chem 275:29955). In the present study, we found that thrombin induced a negative regulator of a cytokine signaling molecule, cytokineinduced SH2 protein (CIS), in rat brain astrocytes. In response to thrombin, CIS expression was increased at both the mRNA and protein levels. Although STAT5 is known to regulate CIS expression, thrombin did not activate STAT5, and inhibitors of JAK2 (AG490) and JAK3 (WHI-P97 and WHI-P154) had little effect on thrombin-induced CIS expression. In contrast, cytosolic phospholipase A 2 (cPLA 2 ), cyclooxygenase (COX), and lipoxygenase (LO) play a role in CIS expression, since inhibitors of cPLA 2 , cyclooxygenase (COX), and LO significantly reduced CIS expression. Reactive oxygen species (ROS) scavengers (N-acetylcysteine [NAC] and trolox) reduced thrombin-induced CIS expression, and inhibitors of COX and LO reduced ROS produced by thrombin. Furthermore, prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ), products of COX and LO, respectively, potentiated thrombin-induced CIS expression, indicating that ROS, and PGE 2 and LTB 4 generated by COX and LO, mediate CIS expression. Since interferon-␥ (IFN-␥)-induced GAS-luciferase activity and tyrosine phosphorylation of STAT1 and STAT3 were lower in CIS-transfected cells compared to control vector-transfected cells, CIS could have anti-inflammatory activity. These data suggest that thrombin-stimulation of ROS and prostaglandin and leukotriene production via the cPLA 2 , COX and LO pathways results in CIS expression. More importantly, CIS expression may be a negative feedback mechanism that prevents prolonged inflammatory responses.

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Cytokine‐inducible SH2 protein‐3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N‐terminal kinase inhibitory region as well as SH2 domain

Cited by 354 publications

References 30 publications

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma

Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A₂, cyclooxygenase, and lipoxygenase

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Cytokine‐inducible SH2 protein‐3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N‐terminal kinase inhibitory region as well as SH2 domain

Cited by 354 publications

References 30 publications

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma

Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A2, cyclooxygenase, and lipoxygenase

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Thrombin induces expression of cytokine‐induced SH2 protein (CIS) in rat brain astrocytes: Involvement of phospholipase A₂, cyclooxygenase, and lipoxygenase