Reduced expression and activity of patient-derived SHIP1 phosphatase domain mutants

Ehm, Patrick; Nelson, Nina; Giehler, Susanne; Schaks, Matthias; Bettin, Bettina; Kirchmair, Johannes; Jücker, Manfred

doi:10.1016/j.cellsig.2022.110485

Cited by 2 publications

(4 citation statements)

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“…Loss of SHIP1 expression could lead to activation of both signaling pathways in T-ALL. Here, experiments targeting phosphatase activity (D672A, G585K and R673Q) and/or the interaction domains and motifs (SH2 domain, PXXP motifs, phosphorylation sites) of SHIP1 [ 21 ] could help, and lead to a significant improvement in our understanding of T-ALL signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations of the INPP5D gene (SHIP1) in hematopoietic and lymphoid cells are rare (107 mutations out of 5936 primary tissue samples tested, corresponding to 1.8% of all tested cases) [ 16 ]. In patients with acute myeloid leukemia (AML), some mutations in the INPP5D gene encoding SHIP1 have been described, thereby implicating mutated SHIP1 in the pathogenesis of AML [ 17 , 18 , 19 , 20 , 21 ]. Mutations of the INPP5D gene can be found only in one T-ALL patient (SHIP1-T1185S) out of 528 samples (0.19%), according to the COSMIC database [ 16 ].…”

Section: Introductionmentioning

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: Introductionmentioning

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%

“…Allosteric binding to SHIP1 by its phosphatase product PI (3,4) P 2 can elevate phosphatase-dependent functions [20][21][22]. In humans, aberrant forms of SHIP1 seen following somatic mutations in cancer [27], abnormal fusion of mRNA transcripts [24], or polymorphisms [30][31][32] can lead to differences in SHIP1 proteasomal degradation or enzymatic function, which contribute to the pathogenesis of cancer, intestinal bowel disease (IBD), and Alzheimer's disease (AD).…”

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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Reduced expression and activity of patient-derived SHIP1 phosphatase domain mutants

Cited by 2 publications

References 29 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

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