Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses

Dallari, Simone; Macal, Mónica; Loureiro, María Eugenia; Jo, Yeara; Swanson, Lee; Hesser, Charles; Ghosh, Pradipta; Zúñiga, Elina I.

doi:10.1038/ncomms14830

Cited by 30 publications

(36 citation statements)

References 67 publications

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“…Especially, we show that LYN, a member of SFK, is involved in the pathogenesis of AD by regulating an oAb 1-42 -FcgRIIb2-SHIP2 pathway in neuronal cells, listing LYN as a neuropathogenic factor in AD. FYN, a member of SFK, is highly homologous to LYN, and much of its function overlaps with LYN in that functional complementation is attained by FYN to mediate allergic responses and plasmacytoid dendritic cell responses in LYN-deficient cells and mice (38,39). As members of SFK share a common regulatory mechanism that determines the phosphorylation status of the Cterminal regulatory domain, it is plausible that both LYN and FYN are activated by oAb under same process (40).…”

Section: Discussionmentioning

confidence: 99%

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Gwon

Kim

et al. 2018

FASEB j.

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SRC‐family kinases (SFKs) have been implicated in Alzheimer's disease (AD), but their mode of action was scarcely understood. Here, we show that LYN plays an essential role in amyloid β (Aβ)‐triggered neurotoxicity and tau hyperphosphorylation by phosphorylating Fcγ receptor IIb2 (FcγRIIb2). We found that enzyme activity of LYN was increased in the brain of AD patients and was promoted in neuronal cells exposed to Aβ 1–42 (Aβ1–42). Knockdown of LYN expression inhibited Aβ1–42‐induced neuronal cell death. Of note, LYN interacted with FcγRIIb2 upon exposure to Aβ1–42 and phosphorylated FcγRIIb2 at Tyr273 within immunoreceptor tyrosine‐based inhibitory motif in neuronal cells. With the use of the structure‐based drug design, we isolated KICG2576, an ATP‐competitive inhibitor of LYN. Determination of cocrystal structure illustrated that KICG2576 bound to the cleft in the LYN kinase domain and inhibited LYN with a half‐maximal inhibitory concentration value of 0.15 µM. KICG2576 inhibited Aβ‐ or FcγRIIb2‐induced cell death, and this effect was better than pyrazolopyrimidine 1, a widely used inhibitor of SFK. Upon exposure to Aβ, KICG2576 blocked the phosphorylation of FcγRIIb2 and translocation of phosphatidylinositol 3,4,5‐trisphosphate 5‐phosphatase 2, a binding protein to the phosphorylated FcγRIIb2, to the plasma membrane, resulting in the inhibition of tau hyperphosphorylation, the downstream event of Aβ1–42‐FcγRIIb2 binding. Furthermore, intracerebroventricular injection of KICG2576 into mice ameliorated Aβ‐induced memory impairment. These results suggest that LYN plays a crucial role in Aβ1–42‐mediated neurotoxicity and tau pathology, providing a therapeutic potential of LYN in AD.—Gwon, Y., Kim, S.‐H., Kim, H. T., Kam, T.‐I., Park, J., Lim, B., Cha, H., Chang, H.‐J., Hong, Y. R., Jung, Y.‐K. Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN. FASEB J. 33, 4300–4313 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Gwon

Kim

et al. 2018

FASEB j.

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“…Among the proteins detected, LYN, a member of Src family kinases (SFK), has been shown its function in the maturation of DC and pDC response 36,37 . Immunoprecipitation confirmed that LYN interacted with STING after DMXAA stimulation in WT BMDC while LYN constitutively interacted with STING in the Fcgr2b-deficient BMDC (Fig.…”

Section: Sting Mediated Maturation Of Conventional DC and Differentiamentioning

confidence: 99%

“…Lyn kinase regulates DC maturation, and genetic deletion of Lyn ablates pDC 36,37 . We hypothesized that STING promoted DC maturation and pDC differentiation through LYN signaling pathway, and the inhibition of LYN should affect the STING-induced BMDC differentiation.…”

Section: Sting Mediated Maturation Of Conventional DC and Differentiamentioning

confidence: 99%

“…6F). However, FYN, a member of the Src family kinases (SFK), has been shown the functional role in pDC maturation and PP2 inhibited both LYN and FYN signaling 37 . Therefore, we identified the colocalization of LYN, FYN, and STING to confirm the protein interaction, and found that LYN, but not FYN, showed the colocalization with STING in the STING-activated BMDC ( Fig.…”

Section: Sting Mediated Maturation Of Conventional DC and Differentiamentioning

confidence: 99%

“…Besides, our study identified several STING-interacting proteins by mass spectrometry. Lyn kinase has been shown the role in the differentiation of pDC 37 . The recruitment of LYN to STING after DMXAA stimulation suggested STING mediated signaling through Lyn kinase.…”

Section: Sting Agonist (Dmxaa) Treated Mice Show the Increased Expresmentioning

confidence: 99%

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Inhibition of Sting rescues lupus disease by the regulation of Lyn-mediated dendritic cell differentiation

Thim-Uam

Prabakaran

Tansakul

et al. 2019

Preprint

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SLE (systemic lupus erythematosus) is an autoimmune disease that causes chronic inflammation and leads to fatality if left untreated. Immune complex-mediated inflammation and type I IFN signaling pathways are one of the mechanisms initiating lupus disease. Signaling through stimulator of interferon genes (STING) leads to the production of type I IFN and inflammatory cytokines. However, the role of STING in lupus mouse models is controversy. Here we demonstrated the mechanisms of STING involving in SLE pathogenesis at the molecular level. The disruption of STING signaling rescued lupus disease in Fcgr2b-deficient mice. STING activated DC facilitated T cell proliferation, which depended on intrinsic expression of STING on DC but not on T cells. Upon STING activation, LYN was recruited and co-localized with STING in bone marrow-derived dendritic cells (BMDC). STING signaling induced phosphorylated LYN and AKT. The inhibition of LYN prohibited STING-induced DC differentiation. Adoptive transfer of STING-activated BMDC into the FCGR2B and STING double-deficiency mice restored lupus phenotypes. These findings provide the proof of concept that inhibition of STING signaling is a promising therapeutic approach for SLE patients.

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Src Family Protein Kinase Controls the Fate of B Cells in Autoimmune Diseases

et al. 2020

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There are more than 80 kinds of autoimmune diseases known at present, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), inflammatory bowel disease (IBD), as well as other disorders. Autoimmune diseases have a characteristic of immune responses directly attacking own tissues, leading to systematic inflammation and subsequent tissue damage. B cells play a vital role in the development of autoimmune diseases and differentiate into plasma cells or memory B cells to secrete highaffinity antibody or provide long-lasting function. Drugs targeting B cells show good therapeutic effects for the treatment of autoimmune diseases, such as rituximab (anti-CD20 antibody). Src family protein kinases (SFKs) are believed to play important roles in a variety of cellular functions such as growth, proliferation, and differentiation of B cell via B cell antigen receptor (BCR). Lck/Yes-related novel protein tyrosine kinase (LYN), BLK (B lymphocyte kinase), and Fyn are three different kinds of SFKs mainly expressed in B cells. LYN has a dual role in the BCR signal. On the one hand, positive signals are beneficial to the development and maturation of B cells. On the other hand, LYN can also inhibit excessively activated B cells. BLK is involved in the proliferation, differentiation, and immune tolerance of B lymphocytes, and further affects the function of B cells, which may lead to autoreactive or regulatory cellular responses, increasing the risk of autoimmune diseases. Fyn may affect the development of autoimmune disorders via the differentiation of B cells in the early stage of B cell development. This article reviews the recent advances of SFKs in B lymphocytes in autoimmune diseases.

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Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses

Cited by 30 publications

References 67 publications

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Amelioration of amyloid β‐FcγRIIb neurotoxicity and tau pathologies by targeting LYN

Inhibition of Sting rescues lupus disease by the regulation of Lyn-mediated dendritic cell differentiation

Src Family Protein Kinase Controls the Fate of B Cells in Autoimmune Diseases

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