Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation

Mkaddem, Sanae Ben; Murua, Amaya; Flament, Héloïse; Titeca-Beauport, Dimitri; Bounaix, Carine; Danelli, Luca; Launay, Pierre; Benhamou, Marc; Blank, Ulrich; Daugas, Éric; Charles, Nicolas; Monteiro, Renato C.

doi:10.1038/s41467-017-00294-0

Cited by 96 publications

(91 citation statements)

References 49 publications

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“…However, data from SLE patients have shown them to have lower levels of Lyn compared to healthy controls, implying that lower levels may be associated with disease . In addition, studies in B cell lines show that Lyn is required for inhibitory signals in response to weak BCR crosslinking . Lyn –/– mice are susceptible to an inducible immune complex–mediated nephritis as well as to antibody‐induced arthritis .…”

Section: Variants Affecting B Cell Signaling Molecules Affect Both Pementioning

confidence: 99%

See 1 more Smart Citation

Review: Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us

Karrar

Graham

2018

Arthritis & Rheumatology

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Section: Variants Affecting B Cell Signaling Molecules Affect Both Pementioning

confidence: 99%

“…In addition, studies in B cell lines show that Lyn is required for inhibitory signals in response to weak BCR crosslinking . Lyn –/– mice are susceptible to an inducible immune complex–mediated nephritis as well as to antibody‐induced arthritis .…”

Section: Variants Affecting B Cell Signaling Molecules Affect Both Pementioning

confidence: 99%

Review: Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us

Karrar

Graham

2018

Arthritis & Rheumatology

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“…Susceptibility to rapid, activation-induced degradation differentiates LynA from the splice variant LynB and the other macrophage SFKs. Hck, Fgr, LynB, and Fyn (17, 19), are degraded >10-fold more slowly than LynA during 3-IB-PP1 treatment (20) (Figure 2A) . Although not expressed in macrophages, Lck is also degraded more slowly than LynA (Figure 2B) .…”

Section: Resultsmentioning

confidence: 99%

“…Multiple mechanisms work together to tune the responsiveness of macrophages and other myeloid cells, including negative regulation by the phosphatases CD45 and CD148 (5, 9, 10), cytoskeletal barriers to diffusion (11), signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) (12) and inhibitory ITAMs (13, 14), and degradation and mislocalization of signaling molecules targeted for polyubiquitination by ubiquitin ligases (15, 16). The SFKs, which in myeloid cells typically include Fgr, Fyn, and two splice forms each of Hck and Lyn, may also have positive and negative functions (12, 17–19). Layered onto the traditional positive-and negative-regulatory roles of the SFKs, we have shown that activated LynA (the longer of the two Lyn splice forms) is rapidly and specifically targeted for polyubiquitination and degradation, forming the basis of a signaling checkpoint that blocks spurious macrophage activation (20).…”

Section: Introductionmentioning

confidence: 99%

An orthogonal c-Cbl recognition mode targets LynA for rapid degradation and builds specificity into the LynA checkpoint

Brian

Nunez

Schwertfeger

et al. 2019

Preprint

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11The activity of Src-family kinases (SFKs), which phosphorylate immunoreceptor tyrosine-based 12 activation motifs (ITAMs), is critical factor regulating myeloid-cell activation. In a previous paper 13 (Freedman et al., 2015) we showed in macrophages that the SFK LynA is uniquely susceptible to rapid 14 ubiquitin-mediated degradation, functioning as a rheostat regulating ITAM signaling. We now report the 15 mechanism by which LynA is preferentially targeted for degradation and how cell specificity is built into 16 the LynA rheostat. Using genetic and biochemical analysis, we found that the E3 ubiquitin ligase c-Cbl 17 preferentially targets LynA via tyrosine 32 in its unique insert region. This orthogonal mode of c-Cbl 18 recognition depresses the steady-state level of macrophage LynA. Mast cells, however, express little c- 19Cbl and have correspondingly high steady-state levels of LynA. Upon activation, mast-cell LynA is not 20 rapidly degraded, and SFK-mediated signaling is amplified relative to macrophages. Cell-specific c-Cbl 21 expression therefore builds cell specificity into the LynA checkpoint. 2245 macrophage activation (20). The mechanism preferentially targeting LynA for polyubiquitination and the 46 molecular basis of this selectivity have not been elucidated previously. 47Unlike Dectin-1 and FcγR signaling in macrophages, which is typically triggered in the context of 48 pathogen-induced µm-scale clusters of receptors (5, 9, 20), mast-cell FcεR signaling has a low 49 threshold for activation--small or even monovalent antigen-IgE complexes are sufficient to induce a 50 signaling response (21, 22). Like macrophages, mast cells express LynA, and this disparity in receptor 51 sensitivity has not previously been explained. This paper describes the mechanism by which active LynA is selectively recognized and rapidly 53 degraded, tuning its activation kinetics and its steady-state protein levels in a cell-specific manner. To 54 reveal the requirements for LynA degradation, we synchronized receptor-independent SFK activation 55 using the designer inhibitor 3-IB-PP1 (23-25), which specifically inhibits a variant of the SFK-inhibitory 56 kinase Csk (Csk AS ) (20, 25, 26). Csk is responsible for phosphorylating a key inhibitory tyrosine in the 57 C-terminus of all the SFKs. Inhibiting Csk AS leads to rapid and robust SFK activation due to the loss of 58 the dynamic equilibrium between Csk and the phosphatases CD45 and CD148 (27, 28). We showed 59 previously that SFK activation induced via 3-IB-PP1 treatment leads to the phosphorylation of the E3 60 ubiquitin ligase c-Cbl and the preferential polyubiquitination and degradation of the SFK LynA, but it 61 was not clear whether these two events were linked. Using knockdown, overexpression, and genetic 62 models, we now demonstrate that c-Cbl, but not its homolog Cbl-b, controls the steady-state expression 63 of LynA and mediates its rapid degradation upon activation in macrophages. LynA is targeted by c-Cbl 64 via a phosphorylation site, Tyr32 within its unique r...

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“…7A-C). In addition, we assessed phosphorylation of SHP-1 on S591, a posttranslational modification induced by PKC and that has been linked to the reduction of phosphatase activity of SHP-1 (39,40), and did not observe any difference under conditions of TAOK3 deficiency.…”

Section: Taok3 Deficiency Is Associated With Enhanced Interaction Betmentioning

confidence: 99%

TAOK3 Regulates Canonical TCR Signaling by Preventing Early SHP-1–Mediated Inactivation of LCK

Ormonde

Stegen

et al. 2018

The Journal of Immunology

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Activation of LCK is required for canonical TCR signaling leading to T cell responses. LCK activation also initiates a negative feedback loop mediated by the phosphatase SHP-1 that turns off TCR signaling. In this article, we report that the thousand-and-one amino acid kinase 3 (TAOK3) is a key regulator of this feedback. TAOK3 is a serine/threonine kinase expressed in many different cell types including T cells. TAOK3-deficient human T cells had impaired LCK-dependent TCR signaling resulting in a defect in IL-2 response to canonical TCR signaling but not to bacterial superantigens, which use an LCK-independent pathway. This impairment was associated with enhanced interaction of LCK with SHP-1 after TCR engagement and rapid termination of TCR signals, a defect corrected by TAOK3 reconstitution. Thus, TAOK3 is a positive regulator of TCR signaling by preventing premature SHP-1–mediated inactivation of LCK. This mechanism may also regulate signaling by other Src family kinase-dependent receptors.

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Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation

Cited by 96 publications

References 49 publications

Review: Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us

Review: Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us

An orthogonal c-Cbl recognition mode targets LynA for rapid degradation and builds specificity into the LynA checkpoint

TAOK3 Regulates Canonical TCR Signaling by Preventing Early SHP-1–Mediated Inactivation of LCK

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