JAK2-V617F is a negative regulation factor of SHIP1 protein and thus influences the AKT signaling pathway in patients with Myeloproliferative neoplasm (MPN)

Glück, Madeleine; Dally, Lina; Jücker, Manfred; Ehm, Patrick

doi:10.1016/j.biocel.2022.106229

Cited by 3 publications

(2 citation statements)

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“…Similar effects can be observed after lentiviral transduction of SHIP1 in the AML cell line UKE1 [56,59]. In contrast, little to no reduction in SHIP1 protein expression was found in two other cell lines (H1299 and Reh), which were handled according to the same routine (Figure S4) [40,59]. In the future, these experiments (determination of the SHIP1 status and reconstitution of SHIP1 expression) should be carried out with other suitable T-ALL cell lines and primary cells.…”

Section: Discussionsupporting

confidence: 71%

“…In contrast, SHIP1 expression is stable at the mRNA level. Similar effects can be observed after lentiviral transduction of SHIP1 in the AML cell line UKE1 [ 56 , 59 ]. In contrast, little to no reduction in SHIP1 protein expression was found in two other cell lines (H1299 and Reh), which were handled according to the same routine ( Figure S4 ) [ 40 , 59 ].…”

Section: Discussionsupporting

confidence: 67%

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SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model

Ehm

Rietow

Wegner

et al. 2023

Cells

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Acute lymphoblastic leukemia (ALL) is the most common cause of cancer-related death in children. Despite significantly increased chances of cure, especially for high-risk ALL patients, it still represents a poor prognosis for a substantial fraction of patients. Misregulated proteins in central switching points of the cellular signaling pathways represent potentially important therapeutic targets. Recently, the inositol phosphatase SHIP1 (SH2-containing inositol 5-phosphatase) has been considered as a tumor suppressor in leukemia. SHIP1 serves as an important negative regulator of the PI3K/AKT signaling pathway, which is frequently constitutively activated in primary T-ALL. In contrast to other reports, we show for the first time that SHIP1 has not been lost in T-ALL cells, but is strongly downregulated. Reduced expression of SHIP1 leads to an increased activation of the PI3K/AKT signaling pathway. SHIP1-mRNA expression is frequently reduced in primary T-ALL samples, which is recapitulated by the decrease in SHIP1 expression at the protein level in seven out of eight available T-ALL patient samples. In addition, we investigated the change in the activity profile of tyrosine and serine/threonine kinases after the restoration of SHIP1 expression in Jurkat T-ALL cells. The tyrosine kinase receptor subfamilies of NTRK and PDGFR, which are upregulated in T-ALL subgroups with low SHIP1 expression, are significantly disabled after SHIP1 reconstitution. Lentiviral-mediated reconstitution of SHIP1 expression in Jurkat cells points to a decreased cellular proliferation upon transplantation into NSG mice in comparison to the control cohort. Together, our findings will help to elucidate the complex network of cell signaling proteins, further support a functional role for SHIP1 as tumor suppressor in T-ALL and, much more importantly, show that full-length SHIP1 is expressed in T-ALL samples.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 67%

SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model

Ehm

Rietow

Wegner

et al. 2023

Cells

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Activated Src kinases downstream of BCR-ABL and Flt3 induces proteasomal degradation of SHIP1 by phosphorylation of tyrosine 1021

Ehm

Bettin

Jücker

2023

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Ikaros sets the threshold for negative B-cell selection by regulation of the signaling strength of the AKT pathway

Ehm,

Horn,

Hoffer

et al. 2024

Cell Commun Signal

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Inhibitory phosphatases, such as the inositol-5-phosphatase SHIP1 could potentially contribute to B-cell acute lymphoblastic leukemia (B-ALL) by raising the threshold for activation of the autoimmunity checkpoint, allowing malignant cells with strong oncogenic B-cell receptor signaling to escape negative selection. Here, we show that SHIP1 is differentially expressed across B-ALL subtypes and that high versus low SHIP1 expression is associated with specific B-ALL subgroups. In particular, we found high SHIP1 expression in both, Philadelphia chromosome (Ph)-positive and ETV6-RUNX1-rearranged B-ALL cells. As demonstrated by targeted knockdown of SHIP1 by RNA interference, proliferation of B-ALL cells in vitro and their tumorigenic spread in vivo depended in part on SHIP1 expression. We investigated the regulation of SHIP1, as an important antagonist of the AKT signaling pathway, by the B-cell-specific transcription factor Ikaros. Targeted restoration of Ikaros and pharmacological inhibition of the antagonistic casein kinase 2, led to a strong reduction in SHIP1 expression and at the same time to a significant inhibition of AKT activation and cell growth. Importantly, the tumor suppressive function of Ikaros was enhanced by a SHIP1-dependent additive effect. Furthermore, our study shows that all three AKT isoforms contribute to the pro-mitogenic and anti-apoptotic signaling in B-ALL cells. Conversely, hyperactivation of a single AKT isoform is sufficient to induce negative selection by increased oxidative stress. In summary, our study demonstrates the regulatory function of Ikaros on SHIP1 expression in B-ALL and highlights the relevance of sustained SHIP1 expression to prevent cells with hyperactivated PI3K/AKT/mTOR signaling from undergoing negative selection.

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JAK2-V617F is a negative regulation factor of SHIP1 protein and thus influences the AKT signaling pathway in patients with Myeloproliferative neoplasm (MPN)

Cited by 3 publications

References 68 publications

SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model

SHIP1 Is Present but Strongly Downregulated in T-ALL, and after Restoration Suppresses Leukemia Growth in a T-ALL Xenotransplantation Mouse Model

Activated Src kinases downstream of BCR-ABL and Flt3 induces proteasomal degradation of SHIP1 by phosphorylation of tyrosine 1021

Ikaros sets the threshold for negative B-cell selection by regulation of the signaling strength of the AKT pathway

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