scholarly journals The Tyrosine Kinase Pyk2 Contributes to Complement-Mediated Phagocytosis in Murine Macrophages

2016 ◽  
Vol 8 (5) ◽  
pp. 437-451 ◽  
Author(s):  
Christoph Paone ◽  
Natalie Rodrigues ◽  
Ella Ittner ◽  
Carina Santos ◽  
Alexander Buntru ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Raw 264.7 ◽  
Raw 264.7 Macrophages ◽  
Pharmacological Inhibition ◽  
Tyrosine Kinase 2 ◽  
C Terminus ◽  
Complement Receptor 3 ◽  
Tat Fusion Protein

Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase (FAK) family and is mainly expressed in neuronal and hematopoietic cells. As FAK family members are involved in signaling connections downstream of integrins, we studied the role of Pyk2 in complement-receptor 3 (CR3, also known as Mac-1, integrin αMβ2, CD11b/CD18)-mediated phagocytosis, a key process in innate immunity. Using 3 independent approaches, we observed that Pyk2 contributes to CR3-dependent phagocytosis by RAW 264.7 macrophages, but is dispensable for Fcγ receptor (FcγR)-mediated uptake. Reduction of Pyk2 expression levels via siRNA, the pharmacological inhibition of Pyk2 kinase activity as well as macrophage treatment with a cell permeable TAT fusion protein containing the C-terminus of Pyk2 (TAT-PRNK) significantly impaired CR3-mediated phagocytosis without affecting FcγR-mediated uptake. In addition, Pyk2 was strongly recruited to complement opsonized Escherichia coli and the pharmacological inhibition of Pyk2 significantly decreased uptake of the bacteria. Finally, CRISPR/Cas-mediated disruption of the pyk2 gene in RAW 264.7 macrophages confirmed the role of this protein tyrosine kinase in CR3-mediated phagocytosis. Together, our data demonstrate that Pyk2 selectively contributes to the coordination of phagocytosis-promoting signals downstream of CR3, but is dispensable for FcγR-mediated phagocytosis.

scholarly journals Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jonghwa Kim ◽  
Wonseok Kang ◽  
So Hee Kang ◽  
Su Hyun Park ◽  
Ji Young Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Tyrosine Kinase ◽  
Focal Adhesion ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Type I ◽  
Tyrosine Kinase 2 ◽  
The Impact ◽  
Tgf Β1

AbstractHepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. We used a CCl4-induced liver fibrosis mice model to evaluate the effect of FAK family kinase inhibitors on liver fibrosis. RT-PCR and Western blot were used to measure the expression of its target genes; α-SMA, collagen, Nox4, TGF-β1, Smad7, and CTGF. Pharmacological inhibitors, siRNA-mediated knock-down, and plasmid-based overexpression were adopted to modulate the function and the expression level of proteins. Association of PYK2 activation with liver fibrosis was confirmed in liver samples from CCl4-treated mice and patients with significant fibrosis or cirrhosis. TGF-β treatment up-regulated expression of α-SMA, type I collagen, NOX4, CTGF, TGF-β1, and Smad7 in LX-2 cells. Inhibition of FAK family members suppressed TGF-β-mediated fibrogenic signaling. SiRNA experiments demonstrated that TGF-β1 and Smad7 were upregulated via Smad-dependent pathway through FAK activation. In addition, CTGF induction was Smad-independent and PYK2-dependent. Furthermore, RhoA activation was essential for TGF-β-mediated CTGF induction, evidenced by using ROCK inhibitor and dominant negative RhoA expression. We identified that TGF-β1-induced activation of PYK2-Src-RhoA triad leads to YAP/TAZ activation for CTGF induction in liver fibrosis. These findings provide new insights into the role of focal adhesion molecules in liver fibrogenesis, and targeting PYK2 may be an attractive target for developing novel therapeutic strategies for the treatment of liver fibrosis.

scholarly journals Lymphocyte-Specific Protein Tyrosine Kinase (LCK) is Involved in the Aryl Hydrocarbon Receptor-Mediated Impairment of Immunoglobulin Secretion in Human Primary B Cells

2018 ◽  
Vol 165 (2) ◽  
pp. 322-334
Author(s):  
Jiajun Zhou ◽  
Qiang Zhang ◽  
Joseph E Henriquez ◽  
Robert B Crawford ◽  
Norbert E Kaminski
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
Aryl Hydrocarbon Receptor ◽  
Protein Tyrosine Kinase ◽  
Specific Protein ◽  
Immunoglobulin M ◽  
Protein Tyrosine ◽  
Immunoglobulin Secretion ◽  
Aryl Hydrocarbon

AbstractThe aryl hydrocarbon receptor (AHR) is a cytosolic ligand-activated transcription factor involved in xenobiotic sensing, cell cycle regulation, and cell development. In humans, the activation of AHR by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AHR-ligand, impairs the secretion of immunoglobulin M (IgM) to suppress humoral immunity. However, the mechanisms bridging the activation of AHR and the impairment of IgM secretion by human primary B cells remain poorly understood. Recent transcriptomic analysis revealed upregulation of lymphocyte-specific protein tyrosine kinase (LCK) in AHR-activated human primary B cells. LCK is a well-characterized tyrosine kinase that phosphorylates critical signaling proteins involved in activation and cytokine production in T cells. Conversely, the role of LCK in human primary B cells is not well understood. In the current studies, we have verified the transcriptomic finding by detecting AHR-mediated upregulation of LCK protein in human primary B cells. We also confirmed the role of AHR in the upregulation of LCK by using a specific AHR antagonist, which abolished the AHR-mediated increase of LCK. Furthermore, we have confirmed the role of LCK in the AHR-mediated suppression of IgM by using LCK specific inhibitors, which restored the IgM secretion by human B cells in the presence of TCDD. Collectively, the current studies demonstrate a novel role of LCK in IgM response and provide new insights into the mechanism for AHR-mediated impairment of immunoglobulin secretion by human primary B cells.

scholarly journals Expression and Oncogenic Role of Brk (PTK6/Sik) Protein Tyrosine Kinase in Lymphocytes

2006 ◽  
Vol 168 (5) ◽  
pp. 1631-1641 ◽  
Author(s):  
Monika Kasprzycka ◽  
Miroslaw Majewski ◽  
Zhi-Jong Wang ◽  
Andrzej Ptasznik ◽  
Maria Wysocka ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Protein Tyrosine

scholarly journals Inhibition of Osteoclast Function by Adenovirus Expressing Antisense Protein-tyrosine Kinase 2

2000 ◽  
Vol 276 (10) ◽  
pp. 7484-7492 ◽  
Author(s):  
Le T. Duong ◽  
Ichiro Nakamura ◽  
Päivi T. Lakkakorpi ◽  
Lorraine Lipfert ◽  
Andrew J. Bett ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Protein Tyrosine ◽  
Tyrosine Kinase 2 ◽  
Osteoclast Function ◽  
Protein Tyrosine Kinase 2
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