The Role of Tyrosine Phosphorylation in Regulation of Signal Transduction Pathways in Unicellular Eukaryotes

Schemarova,

doi:10.21775/cimb.008.027

Cited by 5 publications

(1 citation statement)

References 230 publications

(235 reference statements)

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“…Interestingly, the cytoplasmic domains of some classical and nonclassical a-chains in different species have a conserved tyrosine residue (9, 26) ( Figure 1C). As discussed in the following sections, part of the evidence for reverse MHC-I signaling is supported by the notion that this tyrosine residue can be phosphorylated and that tyrosine phosphorylation is a posttranslational modification frequently involved in signal transduction (27). Besides this, based on their structure, MHC-I molecules belong to the Immunoglobulin (Ig) superfamily, which is widely involved in cellular recognition and intercellular signaling (6,28).…”

Section: Mhc-i Function In T Cell Activation and Nk Cell Regulationmentioning

confidence: 98%

Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types

et al. 2020

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Major histocompatibility complex (MHC) molecules are well-known for their role in antigen (cross-) presentation, thereby functioning as key players in the communication between immune cells, for example dendritic cells (DCs) and T cells, or immune cells and their targets, such as T cells and virus-infected or tumor cells. However, much less appreciated is the fact that MHC molecules can also act as signaling receptors. In this process, here referred to as reverse MHC class I (MHC-I) signaling, ligation of MHC molecules can lead to signal-transduction and cell regulatory effects in the antigen presenting cell. In the case of MHC-I, reverse signaling can have several outcomes, including apoptosis, migration, induced or reduced proliferation and cytotoxicity towards target cells. Here, we provide an overview of studies showing the signaling pathways and cell outcomes upon MHC-I stimulation in various immune and non-immune cells. Signaling molecules like RAC-alpha serine/threonine-protein kinase (Akt1), extracellular signal-regulated kinases 1/2 (ERK1/2), and nuclear factor-κB (NF-κB) were common signaling molecules activated upon MHC-I ligation in multiple cell types. For endothelial and smooth muscle cells, the in vivo relevance of reverse MHC-I signaling has been established, namely in the context of adverse effects after tissue transplantation. For other cell types, the role of reverse MHC-I signaling is less clear, since aspects like the in vivo relevance, natural MHC-I ligands and the extended downstream pathways are not fully known.The existing evidence, however, suggests that reverse MHC-I signaling is involved in the regulation of the defense against bacterial and viral infections and against malignancies. Thereby, reverse MHC-I signaling is a potential target for therapies against viral and bacterial infections, cancer immunotherapies and management of organ transplantation outcomes.

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Section: Mhc-i Function In T Cell Activation and Nk Cell Regulationmentioning

confidence: 98%

Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types

et al. 2020

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Leukocyte immunoglobulin-like receptor B4 regulates key signalling molecules involved in FcγRI-mediated clathrin-dependent endocytosis and phagocytosis

Park¹,

Raftery

Thomas³

et al. 2016

Sci Rep

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FcγRI cross-linking on monocytes may trigger clathrin-mediated endocytosis, likely through interaction of multiple intracellular molecules that are controlled by phosphorylation and dephosphorylation events. However, the identity of phospho-proteins and their regulation are unknown. We proposed the leukocyte immunoglobulin-like receptor B4 (LILRB4) that inhibits FcγRI-mediated cytokine production via Tyr dephosphorylation of multiple kinases, may also regulate endocytosis/phagocytosis through similar mechanisms. FcγRI and/or LILRB4 were antibody-ligated on THP-1 cells, lysates immunoprecipitated using anti-pTyr antibody and peptides sequenced by mass spectrometry. Mascot Search identified 25 Tyr phosphorylated peptides with high confidence. Ingenuity Pathway Analysis revealed that the most significantly affected pathways were clathrin-mediated endocytosis and Fc-receptor dependent phagocytosis. Tyr phosphorylation of key candidate proteins in these pathways included common γ-chain of the Fc receptors, Syk, clathrin, E3 ubiquitin protein ligase Cbl, hepatocyte growth factor-regulated tyrosine kinase substrate, tripartite motif-containing 21 and heat shock protein 70. Importantly, co-ligation of LILRB4 with FcγRI caused significant dephosphorylation of these proteins and was associated with suppression of Fc receptor-dependent uptake of antibody-opsonised bacterial particles, indicating that LILRB4. These results suggest that Tyr phosphorylation may be critical in FcγRI-dependent endocytosis/phagocytosis that may be regulated by LILRB4 by triggering dephosphorylation of key signalling proteins.

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MHC Class I Molecules Exacerbate Viral Infection by Disrupting Type I Interferon Signaling

Xia

Tao

Cui

et al. 2019

Journal of Immunology Research

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MHC class I molecules are key in the presentation of antigen and initiation of adaptive CD8+ T cell responses. In addition to its classical activity, MHC I may possess nonclassical functions. We have previously identified a regulatory role of MHC I in TLR signaling and antibacterial immunity. However, its role in innate antiviral immunity remains unknown. In this study, we found a reduced viral load in MHC I-deficient macrophages that was independent of type I IFN production. Mechanically, MHC I mediated viral suppression by inhibiting the type I IFN signaling pathway, which depends on SHP2. Cross-linking MHC I at the membrane increased SHP2 activation and further suppressed STAT1 phosphorylation. Therefore, our data revealed an inhibitory role of MHC I in type I IFN response to viral infection and expanded our understanding of MHC I and antigen presentation.

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The Role of Tyrosine Phosphorylation in Regulation of Signal Transduction Pathways in Unicellular Eukaryotes

Abstract: The review summarizes for the first time the current concepts of the role of tyrosine phosphorylation in regulation of signal transduction pathways in unicellular eukaryotes. Evolutionary concepts are developed about the origin of protein tyrosine kinases (PTK)-signaling.

Cited by 5 publications

References 230 publications

Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types

Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types

Leukocyte immunoglobulin-like receptor B4 regulates key signalling molecules involved in FcγRI-mediated clathrin-dependent endocytosis and phagocytosis

MHC Class I Molecules Exacerbate Viral Infection by Disrupting Type I Interferon Signaling

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