Autophosphorylation Induces Autoactivation and a Decrease in the Src Homology 2 Domain Accessibility of the Lyn Protein Kinase

Sotirellis, Nikolaos; Johnson, Timothy M.; Hibbs, Margaret L.; Stanley, Irene J.; Stanley, E. Richard; Dunn, Ashley R.; Cheng, Heung‐Chin

doi:10.1074/jbc.270.50.29773

Cited by 52 publications

(27 citation statements)

References 36 publications

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“…Lyn expression was normal at both the protein and mRNA level in B cells from Ets1 −/− mice (Supplemental Figure 1A-B). Phosphorylation of Y508 inhibits Lyn activity, whereas phosphorylation of Y397 stimulates Lyn activity (48). Neither of these phosphorylation events was altered in resting Ets1 −/− B cells (Supplemental Figure 1A), nor was total tyrosine phosphorylation of Lyn (Supplemental Figure 1D).…”

Section: Resultsmentioning

confidence: 99%

A Balance between B Cell Receptor and Inhibitory Receptor Signaling Controls Plasma Cell Differentiation by Maintaining Optimal Ets1 Levels

Luo

Mayeux

Gutierrez

et al. 2014

The Journal of Immunology

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Signaling through the B cell receptor (BCR) can drive B cell activation and contribute to B cell differentiation into antibody-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. Here, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is down regulated in B cells by BCR or TLR signaling through a pathway dependent on PI3 kinase, Btk, IKK2 and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase SHP1 or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.

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Section: Resultsmentioning

confidence: 99%

A Balance between B Cell Receptor and Inhibitory Receptor Signaling Controls Plasma Cell Differentiation by Maintaining Optimal Ets1 Levels

Luo

Mayeux

Gutierrez

et al. 2014

The Journal of Immunology

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“…Several in vitro studies, however, enable us to estimate , the rate of trans-phosphorylation [63], [64]. The rate of dephosphorylation is then chosen to ensure that in resting cells the concentration of phospho-Lyn is low [65].…”

Section: Methodsmentioning

confidence: 99%

A Mathematical Model of CR3/TLR2 Crosstalk in the Context of Francisella tularensis Infection

et al. 2012

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Complement Receptor 3 (CR3) and Toll-like Receptor 2 (TLR2) are pattern recognition receptors expressed on the surface of human macrophages. Although these receptors are essential components for recognition by the innate immune system, pathogen coordinated crosstalk between them can suppress the production of protective cytokines and promote infection. Recognition of the virulent Schu S4 strain of the intracellular pathogen Francisella tularensis by host macrophages involves CR3/TLR2 crosstalk. Although experimental data provide evidence that Lyn kinase and PI3K are essential components of the CR3 pathway that influences TLR2 activity, additional responsible upstream signaling components remain unknown. In this paper we construct a mathematical model of CR3 and TLR2 signaling in response to F. tularensis. After demonstrating that the model is consistent with experimental results we perform numerical simulations to evaluate the contributions that Akt and Ras-GAP make to ERK inhibition. The model confirms that phagocytosis-associated changes in the composition of the cell membrane can inhibit ERK activity and predicts that Akt and Ras-GAP synergize to inhibit ERK.

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“…Phosphorylated ITAMs interact more strongly with the SH2 domains of Lyn and Fyn. Thus, ITAM phosphorylation recruits Lyn and Fyn to receptors (9), which enables activated receptor-dependent trans phosphorylation of the activation-loop tyrosines Y397 and Y420 in receptor-bound Lyn and Fyn, respectively (10, 11). (The numbering of these residues is the same in mouse and human.)…”

Section: Introductionmentioning

confidence: 99%

A Computational Model for Early Events in B Cell Antigen Receptor Signaling: Analysis of the Roles of Lyn and Fyn

Barua

Hlavacek

Lipniacki

2012

The Journal of Immunology

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BCR signaling regulates the activities and fates of B cells. BCR signaling encompasses two feedback loops emanating from Lyn and Fyn, which are Src family protein tyrosine kinases (SFKs). Positive feedback arises from SFK-mediated trans phosphorylation of BCR and receptor-bound Lyn and Fyn, which increases the kinase activities of Lyn and Fyn. Negative feedback arises from SFK-mediated cis phosphorylation of the transmembrane adapter protein PAG1, which recruits the cytosolic protein tyrosine kinase Csk to the plasma membrane, where it acts to decrease the kinase activities of Lyn and Fyn. To study the effects of the positive and negative feedback loops on the dynamical stability of BCR signaling and the relative contributions of Lyn and Fyn to BCR signaling, we consider in this study a rule-based model for early events in BCR signaling that encompasses membrane-proximal interactions of six proteins, as follows: BCR, Lyn, Fyn, Csk, PAG1, and Syk, a cytosolic protein tyrosine kinase that is activated as a result of SFK-mediated phosphorylation of BCR. The model is consistent with known effects of Lyn and Fyn deletions. We find that BCR signaling can generate a single pulse or oscillations of Syk activation depending on the strength of Ag signal and the relative levels of Lyn and Fyn. We also show that bistability can arise in Lyn- or Csk-deficient cells.

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Autophosphorylation Induces Autoactivation and a Decrease in the Src Homology 2 Domain Accessibility of the Lyn Protein Kinase

Cited by 52 publications

References 36 publications

A Balance between B Cell Receptor and Inhibitory Receptor Signaling Controls Plasma Cell Differentiation by Maintaining Optimal Ets1 Levels

A Balance between B Cell Receptor and Inhibitory Receptor Signaling Controls Plasma Cell Differentiation by Maintaining Optimal Ets1 Levels

A Mathematical Model of CR3/TLR2 Crosstalk in the Context of Francisella tularensis Infection

A Computational Model for Early Events in B Cell Antigen Receptor Signaling: Analysis of the Roles of Lyn and Fyn

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