A pleckstrin homology‐related domain in SHIP1 mediates membrane localization during Fcγ receptor‐induced phagocytosis

Ming-Lum, Andrew; Shojania, Shaheen; So, Eva; McCarrell, Erin; Shaw, Eileen; Vu, David M.; Wang, Ida; McIntosh, Lawrence P.; Mui, Alice

doi:10.1096/fj.11-201475

Cited by 29 publications

(31 citation statements)

References 65 publications

(129 reference statements)

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“…Indeed, SHIP1 could be pulled-down from MC lysates by means of a GST-SH3 (Lyn) fusion protein (unpublished data). Recently, a pleckstrin homology-related domain has been identified that is present N-terminal to the 5′-phosphatase domain and shown to mediate membrane localization of SHIP1 by binding to PIP 3 [70]. …”

Section: Reviewmentioning

confidence: 99%

Activation/Inhibition of mast cells by supra-optimal antigen concentrations

Huber

2013

Cell Communication and Signaling

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Mast cells (MCs) are tissue resident cells of hemopoietic origin and are critically involved in allergic diseases. MCs bind IgE by means of their high-affinity receptor for IgE (FcεRI). The FcεRI belongs to a family of multi-chain immune recognition receptors and is activated by cross-linking in response to multivalent antigens (Ags)/allergens. Activation of the FcεRI results in immediate release of preformed granular substances (e.g. histamine, heparin, and proteases), generation of arachidonic acid metabolites, and production of pro-inflammatory cytokines. The FcεRI shows a remarkable, bell-shaped dose-response behavior with weak induction of effector responses at both low and high (so-called supra-optimal) Ag concentrations. This is significantly different from many other receptors, which reach a plateau phase in response to high ligand concentrations. To explain this unusual dose-response behavior of the FcεRI, scientists in the past have drawn parallels to so-called precipitin curves resulting from titration of Ag against a fixed concentration of antibody (Ab) in solution (a.k.a. Heidelberger curves). Thus, for high, supra-optimal Ag concentrations one could assume that every IgE-bound FcεRI formed a monovalent complex with “its own Ag”, thus resulting in marginal induction of effector functions due to absence of receptor cross-linking. However, this was never proven to be the case. More recently, careful studies of FcεRI activation and signaling events in MCs in response to supra-optimal Ag concentrations have suggested a molecular explanation for the descending part of this bell-shaped curve. It is obvious now that extensive FcεRI/IgE/Ag clusters are formed and inhibitory molecules and signalosomes are engaged in response to supra-optimal cross-linking (amongst them the Src family kinase Lyn and the inositol-5′-phosphatase SHIP1) and they actively down-regulate MC effector responses. Thus, the analysis of MC signaling triggered by supra-optimal crosslinking holds great potential for identifying novel targets for pharmacologic therapeutic intervention to benefit patients with acute and chronic allergic diseases.

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Section: Reviewmentioning

confidence: 99%

Activation/Inhibition of mast cells by supra-optimal antigen concentrations

Huber

2013

Cell Communication and Signaling

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“…This “PH‐related” (PH‐R, Fig. ) domain was shown to be required for localization of SHIP to the phagocytic cup in macrophages .…”

Section: Introductionmentioning

confidence: 99%

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

2017

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The phosphoinositide phosphatase SHIP is a critical regulator of immune cell activation. Despite considerable study, the mechanisms controlling SHIP activity to ensure balanced cell activation remain incompletely understood. SHIP dampens BCR signaling in part through its association with the inhibitory coreceptor Fc gamma receptor IIB, and serves as an effector for other inhibitory receptors in various immune cell types. The established paradigm emphasizes SHIP's inhibitory receptor‐dependent function in regulating phosphoinositide 3‐kinase signaling by dephosphorylating the phosphoinositide PI(3,4,5)P3; however, substantial evidence indicates that SHIP can be activated independently of inhibitory receptors and can function as an intrinsic brake on activation signaling. Here, we integrate historical and recent reports addressing the regulation and function of SHIP in immune cells, which together indicate that SHIP acts as a multifunctional protein controlled by multiple regulatory inputs, and influences downstream signaling via both phosphatase‐dependent and ‐independent means. We further summarize accumulated evidence regarding the functions of SHIP in B cells, T cells, NK cells, dendritic cells, mast cells, and macrophages, and data suggesting defective expression or activity of SHIP in autoimmune and malignant disorders. Lastly, we discuss the biological activities, therapeutic promise, and limitations of small molecule modulators of SHIP enzymatic activity.

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“…However, SHIP's lipid product PI(3,4)P 2 is a second messenger and a signaling molecule in its own right. Pertinent to its function in Mϕ phagocytosis, SHIP binding to PI(3,4)P 2 permits its interaction with the phagocytic cup and is required for phagosome closure . Though most studies regarding SHIP's role in mast cells and Mϕs have focused on its phosphatase activity, SHIP may also act as a scaffolding protein, and recent work suggests that SHIP's retention at the cell membrane is critical for global inhibition of cell activation downstream of SHIP recruitment …”

Section: Shipmentioning

confidence: 99%

SHIP negatively regulates type II immune responses in mast cells and macrophages

Dobranowski

Sly

2018

Journal of Leukocyte Biology

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SHIP is a hematopoietic-specific lipid phosphatase that dephosphorylates PI3K-generated PI(3,4,5)-trisphosphate. SHIP removes this second messenger from the cell membrane blunting PI3K activity in immune cells. Thus, SHIP negatively regulates mast cell activation downstream of multiple receptors. SHIP has been referred to as the "gatekeeper" of mast cell degranulation as loss of SHIP dramatically increases degranulation or permits degranulation in response to normally inert stimuli. SHIP also negatively regulates Mϕ activation, including both pro-inflammatory cytokine production downstream of pattern recognition receptors, and alternative Mϕ activation by the type II cytokines, IL-4, and IL-13. In the SHIP-deficient (SHIP ) mouse, increased mast cell and Mϕ activation leads to spontaneous inflammatory pathology at mucosal sites, which is characterized by high levels of type II inflammatory cytokines. SHIP mast cells and Mϕs have both been implicated in driving inflammation in the SHIP mouse lung. SHIP Mϕs drive Crohn's disease-like intestinal inflammation and fibrosis, which is dependent on heightened responses to innate immune stimuli generating IL-1, and IL-4 inducing abundant arginase I. Both lung and gut pathology translate to human disease as low SHIP levels and activity have been associated with allergy and with Crohn's disease in people. In this review, we summarize seminal literature and recent advances that provide insight into SHIP's role in mast cells and Mϕs, the contribution of these cell types to pathology in the SHIP mouse, and describe how these findings translate to human disease and potential therapies.

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A pleckstrin homology‐related domain in SHIP1 mediates membrane localization during Fcγ receptor‐induced phagocytosis

Cited by 29 publications

References 65 publications

Activation/Inhibition of mast cells by supra-optimal antigen concentrations

Activation/Inhibition of mast cells by supra-optimal antigen concentrations

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

SHIP negatively regulates type II immune responses in mast cells and macrophages

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