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

Ehm, Patrick; Bettin, Bettina; Jücker, Manfred

doi:10.1016/j.bbamcr.2023.119467

Cited by 3 publications

(3 citation statements)

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“…However, it is unclear if expression of BCR-ABL contributes to the loss of SHIP1 in Jurkat cells. In fact, it was recently shown that very low (full-length) SHIP1 expression can be found in Jurkat cells [ 58 ]. TCE lysis was an appropriate method for reducing artificial protein degradation by proteases during protein lysis for sensitive detection of SHIP1 expression in T-ALL cells.…”

Section: Discussionmentioning

confidence: 99%

“…The gene expression data in this work also show a clear, negative correlation between the expression of INPP5D (SHIP1) and LCK (especially in G1 vs. G10), the most prominent representative of the Src kinase family in T-cells ( Figure 6 A). Interestingly, it can be shown that Jurkat cells show high Src kinase expression and PP2 (a Src kinase inhibitor) treatment of the Jurkat cells leads to an increase in the expression of SHIP1 [ 58 ]. In summary, NOTCH1, TAL1 and LCK define the G10 subgroup of T-ALL, in which INPP5D (SHIP1) shows a strikingly significantly lower expression.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…In addition, phosphorylation of SHIP1 can lead to several different outcomes, such as increased phosphatase activity [20][21][22], increased ubiquitin-dependent proteasomal degradation [23][24][25][26][27][28][29], and possible phosphotyrosine-mediated interaction with other proteins [7]. Allosteric binding to SHIP1 by its phosphatase product PI (3,4) P 2 can elevate phosphatase-dependent functions [20][21][22].…”

Section: Introduction-ship1 In a Nutshellmentioning

confidence: 99%

SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy

Yeoh,

Krebs

2023

Eur J Immunol

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Phosphoinositide‐3‐kinase/AKT (PI3K/AKT) signaling plays key roles for the regulation of cellular activity in both health and disease. In immune cells, this PI3K/AKT pathway is critically regulated by the phosphoinositide phosphatase SHIP1, which has been reported to modulate the function of most immune subsets. In this review, we summarize our current knowledge of SHIP1 with a focus on innate immune cells, where we reflect on the most pertinent aspects described in the current literature. We also present the several small molecule agonists and antagonists of SHIP1 developed the last two decades, which have led to improved outcomes in several pre‐clinical models of disease. We outline these promising findings and put them in relation with human diseases with unmet medical needs, where we discuss the most attractive targets for immune therapies based on SHIP1 modulation.This article is protected by copyright. All rights reserved

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

Cited by 3 publications

References 77 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

SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy

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

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