Brain Migration Disorder and T-Cell Activation Deficiency Associated with Abnormal Signaling through TCR/CD3 Complex and Hyperactivity of Fyn Tyrosine Kinase*

2000 ◽  
Vol 31 (5) ◽  
pp. 265-268 ◽  
Author(s):  
E. Del Giudice ◽  
L. Gaetaniello ◽  
E. Matrecano ◽  
E. Cosentini ◽  
M.V. Ursini ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Migration Disorder ◽  
Fyn Tyrosine Kinase

scholarly journals A Role for the Tec Family Tyrosine Kinase Txk in T Cell Activation and Thymocyte Selection

1999 ◽  
Vol 190 (10) ◽  
pp. 1427-1438 ◽  
Author(s):  
Connie L. Sommers ◽  
Ronald L. Rabin ◽  
Alexander Grinberg ◽  
Henry C. Tsay ◽  
Joshua Farber ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Positive Selection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Receptor ◽  
Calcium Signal ◽  
Protein Tyrosine

Summary Recent data indicate that several members of the Tec family of protein tyrosine kinases function in antigen receptor signal transduction. Txk, a Tec family protein tyrosine kinase, is expressed in both immature and mature T cells and in mast cells. By overexpressing Txk in T cells throughout development, we found that Txk specifically augments the phospholipase C (PLC)-γ1–mediated calcium signal transduction pathway upon T cell antigen receptor (TCR) engagement. Although Txk is structurally different from inducible T cell kinase (Itk), another Tec family member expressed in T cells, expression of the Txk transgene could partially rescue defects in positive selection and signaling in itk−/− mice. Conversely, in the itk+/+ (wild-type) background, overexpression of Txk inhibited positive selection of TCR transgenic thymocytes, presumably due to induction of cell death. These results identify a role for Txk in TCR signal transduction, T cell development, and selection and suggest that the Tec family kinases Itk and Txk perform analogous functions.

scholarly journals Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56Lck regulates T-cell activation independently of Lck/CD45 interactions

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Matthias Kästle ◽  
Camilla Merten ◽  
Roland Hartig ◽  
Thilo Kaehne ◽  
Ardiyanto Liaunardy-Jopeace ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Enzymatic Activity ◽  
T Cell Activation ◽  
Protein Tyrosine Kinase ◽  
Cell Activation ◽  
Sh2 Domain ◽  
Jurkat T Cells

Abstract Background Upon engagement of the T-cell receptor (TCR), the Src-family protein tyrosine kinase p56Lck phosphorylates components of the TCR (e.g. the TCRζ chains), thereby initiating T-cell activation. The enzymatic activity of Lck is primarily regulated via reversible and dynamic phosphorylation of two tyrosine residues, Y394 and Y505. Lck possesses an additional highly conserved tyrosine Y192, located within the SH2 domain, whose role in T-cell activation is not fully understood. Methods Knock-in mice expressing a phospho-mimetic (Y192E) form of Lck were generated. Cellular and biochemical characterization was performed to elucidate the function of Y192 in primary T cells. HEK 293T and Jurkat T cells were used for in vitro studies. Results Co-immunoprecipitation studies and biochemical analyses using T cells from LckY192E knock-in mice revealed a diminished binding of LckY192E to CD45 and a concomitant hyperphosphorylation of Y505, thus corroborating previous data obtained in Jurkat T cells. Surprisingly however, in vitro kinase assays showed that LckY192E possesses a normal enzymatic activity in human and murine T cells. FLIM/FRET measurements employing an LckY192E biosensor further indicated that the steady state conformation of the LckY192E mutant is similar to Lckwt. These data suggest that Y192 might regulate Lck functions also independently from the Lck/CD45-association. Indeed, when LckY192E was expressed in CD45−/−/Csk−/− non-T cells (HEK 293T cells), phosphorylation of Y505 was similar to Lckwt, but LckY192E still failed to optimally phosphorylate and activate the Lck downstream substrate ZAP70. Furthermore, LckY19E was recruited less to CD3 after TCR stimulation. Conclusions Taken together, phosphorylation of Y192 regulates Lck functions in T cells at least twofold, by preventing Lck association to CD45 and by modulating ligand-induced recruitment of Lck to the TCR. Major findings Our data change the current view on the function of Y192 and suggest that Y192 also regulates Lck activity in a manner independent of Y505 phosphorylation.

scholarly journals T-cell expression of Bruton’s tyrosine kinase promotes autoreactive T-cell activation and exacerbates aplastic anemia

2019 ◽  
Vol 17 (10) ◽  
pp. 1042-1052 ◽  
Author(s):  
Simo Xia ◽  
Xiang Liu ◽  
Xuetao Cao ◽  
Sheng Xu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Aplastic Anemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Autoreactive T Cell

Abstract The role of Bruton’s tyrosine kinase (BTK) in BCR signaling is well defined, and BTK is involved in B-cell development, differentiation, and malignancies. However, the expression of Btk in T cells and its role in T-cell function remain largely unknown. Here, we unexpectedly found high expression and activation of BTK in T cells. Deficiencies in BTK resulted in the impaired activation and proliferation of autoreactive T cells and ameliorated bone marrow failure (BMF) in aplastic anemia. Mechanistically, BTK is activated after TCR engagement and then phosphorylates PLCγ1, thus promoting T-cell activation. Treatment with acalabrutinib, a selective BTK inhibitor, decreased T-cell proliferation and ameliorated BMF in mice with aplastic anemia. Our results demonstrate an unexpected role of BTK in optimal T-cell activation and in the pathogenesis of autoimmune aplastic anemia, providing insights into the molecular regulation of T-cell activation and the pathogenesis of T-cell-mediated autoimmune disease.

The Effects of Imatinib on the Function of Monocyte Derived Dendritic Cells Are Mediated Via the Inhibition of Akt and NF-kappaB Signal Transduction Pathways.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3453-3453
Author(s):  
Anette Rupf ◽  
Silke Appel ◽  
Markus M. Weck ◽  
Frank Grünebach ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Human Monocyte ◽  
Pi3 Kinase ◽  
Imatinib Treatment ◽  
Antigen Uptake

Abstract Imatinib is a novel tyrosine kinase inhibitor effective against Abl kinases, c-Kit and platelet-derived growth-factor receptor (PDGF-R) and is currently used for the treatment of patients with CML and GIST. However, little is known about the effects of imatinib on function and differentiation of non-transformed normal cells. Using this compound, we show that human monocyte derived DC generated in the presence of therapeutic concentrations of imatinib show a concentration dependent reduced expression of CD1a, HLA and co-stimulatory molecules as well as decreased activation-induced secretion of chemokines and cytokines involved in T cell activation. Moreover, exposure to imatinib reduces the capacity of DC to prime T cell responses that cannot be restored by the addition of IL-12 and which is not due to induction of apoptosis or IL-10 secretion. Using Western blot analyses we found that these effects are mediated by a pronounced downregulation of nuclear localized protein levels of NF-kB family members RelB, RelA and NF-kB p50. Furthermore, imatinib treatment inhibited the phosphorylation of Akt, indicating the involvement of the PI3 kinase pathways while not affecting the phosphorylation state of p38 and ERK1 MAP kinase. In line with these results, incubation of monocytes with PI3 kinase inhibitors resulted in a similar phenotype of DC as described above. Gene expression profiling utilizing DNA microarrays revealed upregulation of lysosomal genes and molecules preferentially expressed in monocytes/macrophages. However, in contrast to these observations, imatinib treatment had no effect on the incorporation of latex beads by DC and resulted in a reduced FITC-labeled dextran uptake. Importantly, utilizing blocking antibodies and tyrosine kinase inhibitors we demonstrate that the inhibitory effects of imatinib on DC differentiation are not mediated by PDGF-R and c-Kit but most likely via c-Abl tyrosine kinase. These results demonstrate that imatinib affects the antigen presenting function of DC on several levels: their phenotype, antigen uptake and processing as well as production of cytokines and chemokines.

scholarly journals Modulation of KV1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex

2012 ◽  
Vol 302 (10) ◽  
pp. C1504-C1512 ◽  
Author(s):  
Zerrin Kuras ◽  
Vladimir Kucher ◽  
Scott M. Gordon ◽  
Lisa Neumeier ◽  
Ameet A. Chimote ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Scaffolding Protein ◽  
T Cell Function

The cAMP/PKA signaling system constitutes an inhibitory pathway in T cells and, although its biochemistry has been thoroughly investigated, its possible effects on ion channels are still not fully understood. KV1.3 channels play an important role in T-cell activation, and their inhibition suppresses T-cell function. It has been reported that PKA modulates KV1.3 activity. Two PKA isoforms are expressed in human T cells: PKAI and PKAII. PKAI has been shown to inhibit T-cell activation via suppression of the tyrosine kinase Lck. The aim of this study was to determine the PKA isoform modulating KV1.3 and the signaling pathway underneath. 8-Bromoadenosine 3′,5′-cyclic monophosphate (8-BrcAMP), a nonselective activator of PKA, inhibited KV1.3 currents both in primary human T and in Jurkat cells. This inhibition was prevented by the PKA blocker PKI6–22. Selective knockdown of PKAI, but not PKAII, with siRNAs abolished the response to 8-BrcAMP. Additional studies were performed to determine the signaling pathway mediating PKAI effect on KV1.3. Overexpression of a constitutively active mutant of Lck reduced the response of KV1.3 to 8-Br-cAMP. Moreover, knockdown of the scaffolding protein disc large 1 (Dlg1), which binds KV1.3 to Lck, abolished PKA modulation of KV1.3 channels. Immunohistochemistry studies showed that PKAI, but not PKAII, colocalizes with KV1.3 and Dlg1 indicating a close proximity between these proteins. These results indicate that PKAI selectively regulates KV1.3 channels in human T lymphocytes. This effect is mediated by Lck and Dlg1. We thus propose that the KV1.3/Dlg1/Lck complex is part of the membrane pathway that cAMP utilizes to regulate T-cell function.

scholarly journals Expression of the Receptor Tyrosine Kinase EphB2 on Dendritic Cells Is Modulated by Toll-Like Receptor Ligation but Is Not Required for T Cell Activation

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0138835 ◽  
Author(s):  
Patrice N. Mimche ◽  
Lauren M. Brady ◽  
Shirley Keeton ◽  
David S. J. Fenne ◽  
Thayer P. King ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Activation ◽  
Receptor Tyrosine Kinase ◽  
Cell Activation ◽  
Toll Like Receptor ◽  
Receptor Ligation

A pivotal role of cysteine 3 of Lck tyrosine kinase for localization to glycolipid-enriched microdomains and T cell activation

2001 ◽  
Vol 76 (2) ◽  
pp. 133-138 ◽  
Author(s):  
Atsushi Kosugi ◽  
Fumie Hayashi ◽  
Douglas R. Liddicoat ◽  
Koubun Yasuda ◽  
Shin-ichiroh Saitoh ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
T Cell Activation ◽  
Cell Activation ◽  
Pivotal Role
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