SH2-containing inositol phosphatase (SHIP-1) transiently translocates to raft domains and modulates CD16-mediated cytotoxicity in human NK cells

Galandrini, Ricciarda; Tassi, Ilaria; Mattia, Gianfranco; Lenti, Luisa; Piccoli, Mario; Frati, Luigi; Santoni, Angela

doi:10.1182/blood-2002-04-1058

Cited by 63 publications

(59 citation statements)

References 45 publications

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“…Importantly, at the lower effector-to-target ratios, SHIP1 À/À NK cells exhibited significantly greater ADCC activity following stimulation with IL-12. This finding is an extension of the work conducted by Galandrini et al (17) because this group did not examine the role of SHIP1 in ADCC conducted by cytokine-activated NK cells.…”

Section: Resultssupporting

confidence: 46%

“…In fact, both the extent and duration of Ca 2+ mobilization were enhanced in cells expressing a dominant-negative form of shc, suggesting that recruitment of SHIP1 is necessary for attenuating the activation signals associated with cytotoxicity (18). Importantly, subsequent work has shown that SHIP1 catalytic activity, and not only recruitment to FcR signaling chains, is important in regulating NK cell-mediated cytotoxicity in response to NK-sensitive and antibody-coated targets (17). NK cells overexpressing WT SHIP1 exhibited significantly reduced FcgRIIIa-mediated killing of anti-CD16 mAb-coated tumor targets compared with control cells.…”

Section: Discussionmentioning

confidence: 98%

“…Previous reports investigating the role of SHIP1 in NK cells have shown that upon cross-linking of FcgRIIIa, SHIP1 was phosphorylated and recruited to the~-chain of the FcR signaling complex via its association with the shc adaptor protein, where it exerted inhibitory effects on both NK natural cytotoxicity and ADCC activity (17,18). Specifically, the shc/SHIP1 complex tightly regulated the mobilization of the cytolytic machinery within NK cells (18,39).…”

Section: Discussionmentioning

confidence: 99%

“…Although SHIP1 has been studied extensively in the context of inhibitory FcRs (15,16), its role in NK cell responses initiated by the activation of FcgRIIIa is less well understood. Of note, Galandrini et al (17,18) have shown that FcgRIIIa cross-linking on primary human NK cells induced transient translocation of SHIP1 into lipid raft microdomains, where it associated with the~-chain of the FcR complex and negatively regulated antibody-dependent cellular cytotoxicity (ADCC). Whereas interleukin 12 (IL-12) has long been known for its ability to stimulate NK cell ADCC, it was only recently that our group was able to show that IL-12 also has the ability to markedly enhance the NK cell cytokine response to immobilized IgG, both in preclinical studies and also in the context of a phase I clinical trial of IL-12 and an antibreast cancer antibody (trastuzumab; refs.…”

Section: Introductionmentioning

confidence: 99%

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Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

Parihar¹,

Trotta²,

Roda³

et al. 2005

Cancer Research

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We have previously shown that natural killer (NK) cells secrete a distinct profile of immunomodulatory cytokines in response to dual stimulation with antibody-coated tumor cells and interleukin-12 (IL-12). This NK cell cytokine response is dependent on synergistic signals mediated by the activating receptor for the Fc portion of IgG (Fc;RIIIa) and the IL-12 receptor (IL-12R), both constitutively expressed on NK cells. The phosphatase Src homology 2-containing inositol 5V -phosphatase 1 (SHIP1) is known to exert inhibitory effects on Fc receptor (FcR) signaling via its enzymatic activity on phosphatidylinositol 3-kinase (PI3-K) products within many cells of the immune system, most notably mast cells, B cells, and monocytes. However, its activity in the context of FcR activation on NK cells has not been fully explored. The current study focused on the regulation of Fc;RIIIa-induced NK cell cytokine production by SHIP1. Inhibitor studies showed that NK cell IFN-; production following FcR stimulation in the presence of IL-12 depended, in part, on the downstream products of PI3-K. Overexpression of wild-type (WT) SHIP1, but not a catalytic-deficient mutant, via retroviral transfection of primary human NK cells, resulted in a >70% reduction of NK cell IFN-; production in response to costimulation. In addition, NK cells from SHIP1

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Section: Resultssupporting

confidence: 46%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

Parihar¹,

Trotta²,

Roda³

et al. 2005

Cancer Research

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“…SHIP is recruited by engagement of the inhibitory Fc receptor in B cells and mast cells (5)(6)(7)(8) or by the engagement of FcRs (Fc RI and Fc␥RIII), cytokine [interleukin 3 (IL3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TGF␤], and growth factor (steel factor and M-CSF) receptors in myeloid cells (2,9). Once SHIP is recruited to the membrane by the signaling complexes, its enzymatic activity depletes PI(3,4,5)P 3 and prevents membrane localization of PHdomain-containing factors such as Tec kinases, Akt, and PLC␥ (10)(11)(12)(13). This inhibitory effect ultimately leads to reduced calcium influx and prevents cellular activation (14).…”

mentioning

confidence: 99%

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

Тарасенко

Kole

Anthony

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The 5 -phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficient T cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Th1-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8 ؉ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity.cytotoxicity ͉ T-bet T he 5Ј-inositol phosphatase SHIP is a well characterized inhibitory molecule that regulates cell responses in lymphocytes and myeloid cells by its ability to hydrolyze the second messenger PI(3,4,5) trisphosphate (1-4). SHIP is recruited by engagement of the inhibitory Fc receptor in B cells and mast cells (5)(6)(7)(8) or by the engagement of FcRs (Fc RI and Fc␥RIII), cytokine [interleukin 3 (IL3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TGF␤], and growth factor (steel factor and M-CSF) receptors in myeloid cells (2, 9). Once SHIP is recruited to the membrane by the signaling complexes, its enzymatic activity depletes PI(3,4,5)P 3 and prevents membrane localization of PHdomain-containing factors such as Tec kinases, Akt, and PLC␥ (10-13). This inhibitory effect ultimately leads to reduced calcium influx and prevents cellular activation (14).Germ-line deletion of SHIP in mice leads to early mortality from a myeloproliferative-like syndrome characterized by profound splenomegaly and massive myeloid infiltration of the lung (15). B cells develop abnormally in SHIP-null mice, with an activated phenotype and specifically lacking the marginal zone B cell population (16,17). The absence of marginal-zone B cells in SHIP-null mice has been explained not as a B cell primary defect, but as a consequence of macrophage dysregulation in the spleen of these animals (17). Macrophages from SHIP-null mice are skewed toward an M2-activated phenotype showing high levels of arginase I (ArgI) and Ym1. R...

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FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer

et al. 2022

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Low-affinity immunoglobulin gamma Fc region receptor III-A (FccRIIIa) is a cell surface protein that belongs to a family of Fc receptors that facilitate the protective function of the immune system against pathogens. However, the role of FccRIIIa in prostate cancer (PCa) progression remained unknown. In this study, we found that FccRIIIa expression was present in PCa cells and its level was significantly higher in metastatic lesions than in primary tumors from the PCa cohort (P = 0.006). PCa patients with an elevated level of FccRIIIa expression had poorer biochemical recurrence (BCR)-free survival compared with those with lower FccRIIIa expression, suggesting that FccRIIIa is of clinical importance in PCa. We demonstrated that overexpression of FccRIIIa increased the proliferative ability of PCa cell line C4-2 cells, which was accompanied by the upregulation of androgen receptor (AR) and phosphatidylinositol-4-phosphate 5-kinase alpha (PIP5Ka), which are the key players in controlling PCa progression. Conversely, targeted inhibition of FccRIIIa via siRNA-mediated knockdown or using its inhibitory antibody suppressed growth of xenograft PC-3 and PC-3M prostate tumors and reduced distant metastasis in xenograft mouse models. We further showed that elevated expression of AR enhanced FccRIIIa expression, whereas inhibition of AR activity using enzalutamide led to a significant downregulation of FccRIIIa protein expression. Similarly, inhibition of PIP5K1a decreased FccRIIIa expression Abbreviations ALDH, aldehyde dehydrogenases; AR, androgen receptor; ARE-Luc vector, androgen-responsive element luciferase vector; BPH, benign prostate hyperplasia; BRFS, biochemical recurrence-free survival; CRPC, castration-resistant prostate cancer; DHT, dihydrotestosterone; FccRIIIa, low-affinity immunoglobulin gamma Fc region receptor III-A; GDPR, The General Data Protection Regulation; PCa, prostate cancer; PIP2, phosphatidylinositol-4,5-P 2 ; PIP5K1a, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha.

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SH2-containing inositol phosphatase (SHIP-1) transiently translocates to raft domains and modulates CD16-mediated cytotoxicity in human NK cells

Cited by 63 publications

References 45 publications

Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

FcγRIIIa receptor interacts with androgen receptor and PIP5K1α to promote growth and metastasis of prostate cancer

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