SOCS2: inhibitor of JAK2V617F-mediated signal transduction

Quentmeier, Hilmar; Geffers, Robert; Jost, Edgar; MacLeod, Roderick A.F.; Nagel, Stefan; Röhrs, Sonja; Romani, Julia; Scherr, Michaela; Zaborski, Margarete; Drexler, Hans G.

doi:10.1038/leu.2008.226

Cited by 41 publications

(42 citation statements)

References 29 publications

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“…They are a cytokine-independent cell line showing a low expression of the negative regulator SOCS-2. 31 These cells provided us an alternative model for a JAK2-driven disease and we could show that SB1518 potently blocked JAK/STAT signaling in tumor tissue after both acute and chronic dosing (Figures 5a and c). SB1518 also effectively blocked tumor growth in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 95%

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Hart¹,

Goh²,

et al. 2011

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SB1518 is an innovative pyrimidine-based macrocycle that shows a unique kinase profile with selective inhibition of Janus Kinase-2 (JAK2; IC 50 ¼ 23 and 19 nM for JAK2 WT and JAK2 V617F , respectively) within the JAK family (IC 50 ¼ 1280, 520 and 50 nM for JAK1, JK3 and TYK2, respectively) and fms-like tyrosine kinase-3 (FLT3; IC 50 ¼ 22 nM). SB1518 shows potent effects on cellular JAK/STAT pathways, inhibiting tyrosine phosphorylation on JAK2 (Y221) and downstream STATs. As a consequence SB1518 has potent anti-proliferative effects on myeloid and lymphoid cell lines driven by mutant or wild-type JAK2 or FLT3, resulting from cell cycle arrest and induction of apoptosis. SB1518 has favorable pharmacokinetic properties after oral dosing in mice, is well tolerated and significantly reduces splenomegaly and hepatomegaly in a JAK2 V617F -driven disease model. SB1518 dose-dependently inhibits intra-tumor JAK2/ STAT5 signaling, leading to tumor growth inhibition in a subcutaneous model generated with SET-2 cells derived from a JAK2 V617F patient with megakaryoblastic leukemia. Moreover, SB1518 is active against primary erythroid progenitor cells sampled from patients with myeloproliferative disease. In summary, SB1518 has a unique profile and is efficacious and well tolerated in JAK2-dependent models. These favorable properties are now being confirmed in clinical studies in patients with myelofibrosis and lymphoma.

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Section: Discussionmentioning

confidence: 95%

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Hart¹,

Goh²,

et al. 2011

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“…33 Interestingly, Lnk and SOCS2 can inhibit cytokine signaling through interaction with both the cytokine receptor and JAK2. 11,18,32 In contrast, SOCS3, who acts mainly on the kinase, is unable to inhibit JAK2-V617F, but rather enhances its kinase activity.…”

Section: Discussionmentioning

confidence: 99%

Expression level and differential JAK2-V617F–binding of the adaptor protein Lnk regulates JAK2-mediated signals in myeloproliferative neoplasms

Baran‐Marszak

Magdoud

Desterke

et al. 2010

Blood

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“…The SOCS3-F136L mutation was found in 3 out of 127 patients and 2 out of 160 healthy donors. In addition to the mutation in the SOCS3 gene, hypermethylation of the SOCS1, SOCS2 and SOCS3 genes or deletion of the SOCS2 gene was reported in patients with myeloproliferative disorder [92][93][94][95].…”

Section: Socs Proteins In Rtk Regulated Diseasesmentioning

confidence: 99%

SOCS proteins in regulation of receptor tyrosine kinase signaling

Kazi

Kabir

Flores‐Morales

2014

Cell. Mol. Life Sci.

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SOCS proteins in regulation of receptor tyrosine kinase signaling.Uddin, Kazi; Kabir, Nuzhat N; Flores-Morales, Amilcar; Rönnstrand, Lars Link to publication Citation for published version (APA): Kazi, J. U., Kabir, N. N., Flores-Morales, A., & Rönnstrand, L. (2014). SOCS proteins in regulation of receptor tyrosine kinase signaling. Cellular and Molecular Life Sciences, 71(17), 3297-3310. DOI: 10.1007/s00018-014-1619-y General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. AbstractThe receptor tyrosine kinases (RTKs) are a family of cell surface receptors that play critical roles in signal transduction from extracellular stimuli. Many of this family of kinases are overexpressed or mutated in human malignancies and thus became attractive drug target for cancer treatment. The signaling mediated by RTKs must be tightly regulated by interacting proteins including protein-tyrosine phosphatases and ubiquitin ligases. The suppressor of cytokine signaling (SOCS) family proteins are well known negative regulators of cytokine receptors signaling consisting of eight structurally similar proteins, SOCS1-7 and CIS. A key feature of this family of proteins is the presence of an SH2 domain and a SOCS box. Recent studies suggest that SOCS proteins also play a role in RTK signaling. Activation of RTK results in transcriptional activation of SOCS encoding genes. These proteins associate with RTKs through their SH2 domains and subsequently recruit the E3 ubiquitin machinery through the SOCS box, and thereby limit receptor stability by inducing ubiquitination. In a similar fashion SOCS proteins negatively regulate mitogenic signaling by RTKs. It is also evident that RTKs sometimes can bypass SOCS regulation and SOCS proteins can even potentiate RTKs-mediated mitogenic signaling. Thus apart from negative regulation of receptor signaling, SOCS proteins may also influence signaling in other ways.

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SOCS2: inhibitor of JAK2V617F-mediated signal transduction

Cited by 41 publications

References 29 publications

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

Expression level and differential JAK2-V617F–binding of the adaptor protein Lnk regulates JAK2-mediated signals in myeloproliferative neoplasms

SOCS proteins in regulation of receptor tyrosine kinase signaling

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