Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in mice

Sharma, Namit; Everingham, Stephanie; Zeng, Li; Zhang, Zhong Yin; Kapur, Reuben; Craig, Andrew W.B.

doi:10.18632/oncotarget.2177

Cited by 13 publications

(13 citation statements)

References 42 publications

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“…IL-3, c-Kit and IKKs are involved in pathogenesis of a number of malignancies [43–45]. Therefore, we determined the activation status of IKKs and their relevance for survival and proliferation in tumor mast cells.…”

Section: Resultsmentioning

confidence: 99%

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells

et al. 2015

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Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2+-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term “subthreshold IKK activation”.This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33.We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo.Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.

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Section: Resultsmentioning

confidence: 99%

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells

et al. 2015

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“…During erythropoiesis, mice harboring a PTPN11 D61Y mutation have been observed to hyper-expand early-stage pro-erythroblasts, with heightened Stat3, Akt and Erk activation also exhibited 122 . In studies by Sharma et al 123, 124 , PTPN11 also has been shown to be a mediator of oncogenic KIT effects on mastocytosis. PTPN11 therefore acts predominantly as an overall positive effector within select type 1 cytokine receptor and RTK systems.…”

Section: ] Potential Targeting Of Signal Transducers Downstream Of Tmentioning

confidence: 97%

“…In EPOR and anemia contexts, targeting PTPN11 is counter-intuitive due to its predominant roles as a positive effector 118, 119, 121, 122, 124 . PTPN11 inhibitors, however, are successfully being developed for candidate use in juvenile myelomonocytic leukemia and Noonan disease 129-131 .…”

Section: ] Potential Targeting Of Signal Transducers Downstream Of Tmentioning

confidence: 99%

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

Rainville

Jachimowicz

Wojchowski

2015

Expert Opinion on Therapeutic Targets

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Introduction Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy) and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly and may affect cancer progression. Potential high merit therefore exists for defining new targets for anti-anemia agents within EPO, and EPO receptor (EPOR) regulatory circuits. Areas covered EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases and HIF2a acetylases, each with potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer (together with JAK2), and novel agents that trigger EPOR complex activation also remain attractive to develop (activating antibodies, mimetics, small molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be drugable including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases. Expert Opinion While rhEPO (and biosimilars) presently are important mainstay erythropoiesis-stimulating agents, impetus exists for studies of novel ESAs that fortify HIF2a’s effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects and/or costs.

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“…Moreover, mouse myeloid progenitors and leukaemic cells caused by E76K mutation are sensitive to this inhibitor [54]. Another molecule, II-B08, can inhibit SHP-2 and strongly bind to the receptor [55] and thereby enhances the effects of dasatinib on human and mouse mastocytoma cells.…”

Section: Shp-2mentioning

confidence: 99%

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

et al. 2018

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Well-balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, diﬀerentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in haematopoietic cells are SHP-1 and SHP-2. SHP-1, 2 promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP is another inhibitory phosphatase that is specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and SHIP deficiency results in myeloproliferation and B-cell lymphoma in mice. The validation of SHP-1, 2 and SHIP as oncology targets has generated interest in the development of inhibitors as potential therapeutic agents for cancers; however, SHP-1, 2 and SHIP have proven to be an extremely diﬃcult target for drug discovery, primarily due to the highly conserved and positively charged nature of their PTP active site, and many PTP inhibitors lack either appropriate selectivity or membrane permeability. To overcome these caveats, novel techniques have been employed to synthesise new inhibitors that specifically attenuate the PTP-dependent signaling inside the cell and amongst them; some are already in clinical development which are discussed in this review.

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Oncogenic KIT-induced aggressive systemic mastocytosis requires SHP2/PTPN11 phosphatase for disease progression in mice

Cited by 13 publications

References 42 publications

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?

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