scholarly journals The Bmx Tyrosine Kinase Induces Activation of the Stat Signaling Pathway, Which Is Specifically Inhibited by Protein Kinase Cδ

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4341-4353 ◽  
Author(s):  
Pipsa Saharinen ◽  
Niklas Ekman ◽  
Krista Sarvas ◽  
Peter Parker ◽  
Kari Alitalo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Mammalian Cells ◽  
Stat Proteins ◽  
Stat Signaling ◽  
Tec Family Kinase ◽  
A Tec

Abstract Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exemplified by the crucial role of Btk for B-cell differentiation and activation. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and substrate molecules used by Tec kinases are still largely unknown. In this study a Tec family kinase, Bmx, was found to induce activation of the Stat signaling pathway. Bmx induced the tyrosine phosphorylation and DNA binding activity of all the Stat factors tested, including Stat1, Stat3, and Stat5, both in mammalian and insect cells. Bmx also induced transcriptional activation of Stat1- and Stat5-dependent reporter genes. Other cytoplasmic tyrosine kinases, Syk, Fyn, and c-Src, showed no or only weak ability to activate Stat proteins. Expression of Bmx in mammalian cells was found to induce activation of endogenous Stat proteins without activation of endogenous Jak kinases. We further analyzed the Bmx-mediated activation of Stat1, which was found to be regulated by protein kinase C δ (PKCδ) isoform, but not β 1, ε, or ζ isoforms, leading to inhibition of Stat1 tyrosine phosphorylation. In conclusion, these studies show that Bmx, a Tec family kinase, can function as an activator of the Stat signaling pathway and identify a role for PKCδ in the regulation of Bmx signaling.

scholarly journals The Bmx Tyrosine Kinase Induces Activation of the Stat Signaling Pathway, Which Is Specifically Inhibited by Protein Kinase Cδ

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4341-4353 ◽  
Author(s):  
Pipsa Saharinen ◽  
Niklas Ekman ◽  
Krista Sarvas ◽  
Peter Parker ◽  
Kari Alitalo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Mammalian Cells ◽  
Stat Proteins ◽  
Stat Signaling ◽  
Tec Family Kinase ◽  
A Tec

Members of the hematopoietically expressed Tec tyrosine kinase family have an important role in hematopoietic signal transduction, as exemplified by the crucial role of Btk for B-cell differentiation and activation. Although a variety of cell surface receptors have been found to activate Tec tyrosine kinases, the specific signaling pathways and substrate molecules used by Tec kinases are still largely unknown. In this study a Tec family kinase, Bmx, was found to induce activation of the Stat signaling pathway. Bmx induced the tyrosine phosphorylation and DNA binding activity of all the Stat factors tested, including Stat1, Stat3, and Stat5, both in mammalian and insect cells. Bmx also induced transcriptional activation of Stat1- and Stat5-dependent reporter genes. Other cytoplasmic tyrosine kinases, Syk, Fyn, and c-Src, showed no or only weak ability to activate Stat proteins. Expression of Bmx in mammalian cells was found to induce activation of endogenous Stat proteins without activation of endogenous Jak kinases. We further analyzed the Bmx-mediated activation of Stat1, which was found to be regulated by protein kinase C δ (PKCδ) isoform, but not β 1, ε, or ζ isoforms, leading to inhibition of Stat1 tyrosine phosphorylation. In conclusion, these studies show that Bmx, a Tec family kinase, can function as an activator of the Stat signaling pathway and identify a role for PKCδ in the regulation of Bmx signaling.

Anaplastic Lymphoma Kinase Is Activated through the Pleiotrophin/Receptor Protein Tyrosine Phosphatase (RPTP)β/ζ Signaling Pathway: A Unique Mechanism of Activation of Receptor Protein Tyrosine Kinases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4355-4355
Author(s):  
Pablo Perez-Pinera ◽  
Wei Zhang ◽  
Zhaoyi Wang ◽  
James R. Berenson ◽  
Thomas F. Deuel
Keyword(s):  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Anaplastic Lymphoma ◽  
Unique Mechanism

Abstract Anaplastic Lymphoma Kinase (ALK) is a receptor-type transmembrane tyrosine kinase (RTK) of the insulin receptor superfamily that structurally is most closely related to leukocyte tyrosine kinase. It was first discovered as a chimeric protein (NPM-ALK) of nucleophosmin and the C-terminal (kinase) domain of ALK in anaplastic large cell lymphomas (ALCL). NPM-ALK is constitutively active and generates the oncogenic signals that are the pathogenic mechanisms of these highly malignant cancers. The full-length ALK also is believed to have an important role in the pathogenesis of other human malignancies, since its expression is found in rhabdomyosarcomas, neuroblastomas, neuroectodermal tumors, glioblastomas, breast carcinomas, and melanomas. Recently it was proposed that pleiotrophin (PTN the protein, Ptn the gene) is the ligand that stimulates ALK to transduce signals to activate downstream targets. However, this proposal contrasted with earlier studies that demonstrated Receptor Protein Tyrosine Phosphatase (RPTP)β/ζ is the functional receptor for PTN. PTN was shown to inactivate RPTPβ/ζ and thereby permit the activity of different tyrosine kinases to increase tyrosine phosphorylation of the substrates of RPTPβ/ζ at the sites that are dephosphorylated by RPTPβ/ζ in cells not stimulated by PTN. Subsequent studies identified β-catenin, β-adducin, Fyn, GIT1/Cat-1, P190RhoGAP, and histone deacetylase 2 (HDAC-2) as downstream targets of the PTN/RPTPβ/ζ signaling pathway and demonstrated that their levels of tyrosine phosphorylation increase in PTN-stimulated cells. This diversity of PTN-regulated targets is one basis for the pleiotrophic activities of PTN. We now demonstrate that tyrosine phosphorylation of ALK is increased in PTN-stimulated cells through the PTN/RPTPβ/ζ signaling pathway. It is furthermore shown that ALK is activated in PTN-stimulated cells when it is expressed in cells without its extracellular domain, that β-catenin is a substrate of ALK, that the tyrosine phosphorylation site in β-catenin phosphorylated by ALK is the same site dephosphorylated by RPTPβ/ζ, and that PTN-stimulated tyrosine phosphorylation of β-catenin requires expression of ALK. The data suggest a unique mechanism to activate ALK; the data support a mechanism in which β-catenin is phosphorylated in tyrosine through the coordinated inactivation of RPTPβ/ζ, the activation of the tyrosine kinase activity of ALK, and the phosphorylation of β-catenin by ALK at the same site regulated by RPTPβ/ζ in PTN-stimulated cells. Since PTN often is inappropriately expressed in the same malignancies that express ALK, the data suggest a mechanism through which ALK signaling may contribute to those malignancies that express full length ALK through the activity of PTN to signal constitutively the same pathways as NPM-ALK in ALCL.

Tyrosine kinase-dependent calcium signaling in airway smooth muscle cells

2000 ◽  
Vol 278 (6) ◽  
pp. L1138-L1145 ◽  
Author(s):  
Barbara Tolloczko ◽  
Florence C. Tao ◽  
Mary E. Zacour ◽  
James G. Martin
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Calcium Signaling ◽  
Tyrosine Phosphorylation ◽  
Airway Smooth Muscle ◽  
Tyrosine Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Airway Smooth Muscle Cells ◽  
Mitogen Activated Protein

Contractile agonists may stimulate mitogenic responses in airway smooth muscle by mechanisms that involve tyrosine kinases. The role of contractile agonist-evoked activation of tyrosine kinases in contractile signaling is not clear. We addressed this issue using cultured rat airway smooth muscle cells. In these cells, serotonin (5-HT, 1 μM) caused contraction (quantitated by a decrease in cell area), which was blocked by the tyrosine kinase inhibitor genistein (40 μM). Genistein and tyrphostin 23 (40 and 10 μM, respectively) significantly decreased 5-HT-evoked peak Ca2+ responses, and the effect of genistein could be observed in the absence of extracellular Ca2+. The specific inhibitor of mitogen-activated protein kinase kinase PD-98059 (30 μM) had no significant effect on peak Ca2+ levels. Western analysis of cell extracts revealed that 5-HT caused a significant increase in tyrosine phosphorylation of proteins with molecular masses of ∼70 kDa within 10 s of stimulation but no measurable tyrosine phosphorylation of the γ isoform of phospholipase C (PLC-γ). Tyrosine phosphorylation was inhibited by genistein. Furthermore, genistein (40 μM) significantly attenuated 5-HT-induced inositol phosphate production. We conclude that in airway smooth muscle contractile agonists acting on G protein-coupled receptors may activate tyrosine kinase(s), which in turn modulate calcium signaling by affecting, directly or indirectly, PLC-β activity. It is unlikely that PLC-γ or the mitogen-activated protein kinase pathway is involved in Ca2+ signaling to 5-HT.

Targeting the JAK/STAT Signaling Pathway for Breast Cancer.

2020 ◽  
Vol 28 ◽  
Author(s):  
Fei Shao ◽  
Xiaonan Pang ◽  
Gyeong Hun Baeg
Keyword(s):  
Breast Cancer ◽  
Signal Transduction ◽  
Signaling Pathway ◽  
Signal Transduction Pathway ◽  
Breast Cancer Treatment ◽  
Review Article ◽  
Transduction Pathway ◽  
Inhibitory Effects ◽  
Stat Proteins ◽  
Stat Signaling

Abstract:: Breast cancer is the most common malignant tumor in women worldwide. Traditional ways of treatment, includ-ing radiotherapy and endocrine therapy, for breast cancer have inevitable side effects. In recent decades, targeted therapies for breast cancer have rapidly advanced and shown a promising future. The JAK/STAT signaling pathway has been shown to play important roles in tumorigenesis, maintenance and metastasis of breast cancer. Hence, many small molecule inhibi-tors of JAK and STAT proteins have been developed. These inhibitors exhibit potent inhibitory effects on breast cancer in both cellular and animal models, and even some of them have already been in clinical trials. This review article discussed the JAK/STAT signal transduction pathway in the pathogenesis of breast cancer, and the potential for the application of JAK/STAT inhibitors in breast cancer treatment.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

Involvement of proline-rich tyrosine kinase 2 in platelet activation: tyrosine phosphorylation mostly dependent on αIIbβ3 integrin and protein kinase C, translocation to the cytoskeleton and association with Shc through Grb2

2000 ◽  
Vol 347 (2) ◽  
pp. 561-569 ◽  
Author(s):  
Tsukasa OHMORI ◽  
Yutaka YATOMI ◽  
Naoki ASAZUMA ◽  
Kaneo SATOH ◽  
Yukio OZAKI
Keyword(s):  
Protein Kinase C ◽  
Platelet Aggregation ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Human Platelets ◽  
Sh2 Domain ◽  
Kinase C ◽  
Tyrosine Kinase 2 ◽  
Αiibβ3 Integrin

Proline-rich tyrosine kinase 2 (Pyk2) (also known as RAFTK, CAKβ or CADTK) has been identified as a member of the focal adhesion kinase (FAK) family of protein-tyrosine kinases and it has been suggested that the mode of Pyk2 activation is distinct from that of FAK. In the present study we investigated the mode of Pyk2 activation in human platelets. When platelets were stimulated with thrombin, Pyk2, as well as FAK, was markedly tyrosine-phosphorylated, in a manner mostly dependent on αIIbβ3 integrin-mediated aggregation. The residual Pyk2 tyrosine phosphorylation observed in the absence of platelet aggregation was completely abolished by pretreatment with BAPTA/AM [bis-(o-aminophenoxy)ethane-N,N,Nʹ,Nʹ-tetra-acetic acid acetoxymethyl ester]. The Pyk2 phosphorylation was inhibited by protein kinase C (PKC) inhibitors at concentrations that inhibited platelet aggregation. In contrast, direct activation of PKC with the active phorbol ester PMA induced the tyrosine phosphorylation of Pyk2 and FAK but only when platelets were fully aggregated with the exogenous addition of fibrinogen (the ligand for αIIbβ3 integrin). Furthermore, PMA-induced Pyk2 (and FAK) tyrosine phosphorylation was also observed when platelets adhered to immobilized fibrinogen. The activation of the von Willebrand factor (vWF)--glycoprotein Ib pathway with botrocetin together with vWF failed to induce Pyk2 (and FAK) tyrosine phosphorylation. Most Pyk2 and FAK was present in the cytosol and membrane skeleton fractions in unstimulated platelets. When platelets were stimulated with thrombin, both Pyk2 and FAK were translocated to the cytoskeleton in an aggregation-dependent manner. In immunoprecipitation studies, Pyk2, as well as FAK, seemed to associate with Shc through Grb2. With the use of glutathione S-transferase fusion proteins containing Shc-SH2, Grb2-SH2, and Grb2 N-terminal and C-terminal SH3 domains, it was implied that the proline-rich region of Pyk2 (and FAK) binds to the N-terminal SH3 domain of Grb2 and that the phosphotyrosine residue of Shc binds to the SH2 domain of Grb2. Although Pyk2 and FAK have been reported to be differentially regulated in many cell types, our results suggest that, in human platelets, the mode of Pyk2 activation is mostly similar to that of FAK, in terms of αIIbβ3 integrin-dependent and PKC-dependent tyrosine phosphorylation. Furthermore, Pyk2, as well as FAK, might have one or more important roles in post-aggregation tyrosine phosphorylation events, in association with the cytoskeleton and through interaction with adapter proteins including Grb2 and Shc.

scholarly journals Anlotinib Induced Apoptosis and Regulated the Chemosensitivity and Immune-Related Properties of Leukemia Stem Cells By Inhibiting JAK2-STAT3/5 Signaling

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-12
Author(s):  
Long Liu ◽  
Long Yue Jiang ◽  
Bing Xu
Keyword(s):  
Stem Cells ◽  
Tyrosine Kinase ◽  
Immune Evasion ◽  
Tyrosine Kinases ◽  
Receptor Expression ◽  
The Self ◽  
Leukemia Stem Cells ◽  
Self Renewal ◽  
Stat Signaling ◽  
Apoptotic Proteins

Acute myeloid leukemia (AML) is derived from small populations of leukemia stem cells (LSCs) characterized by the self-renewal and chemoresistant properties. Residual LSCs after chemotherapy remain as the critical barriers to cure. Clearance of LSCs might rationally lead to an improvement of clinical outcome. Recently studies showed that JAK/STAT signaling play an important role in the self-renewal of AML-LSCs due to increased growth factor (GF) receptor expression such as c-kit, FLT3, CD123 and altered GF signaling by activating tyrosine kinases. Therefore, targeting such tyrosine kinases might be a strategy to eliminate LSCs. Anlotinib displayed its anti-tumor activity in lung cancer by targeting tyrosine kinase of VEGFR, FGFR, PDGFR and c-kit. However, whether anlotinib could inhibit the GF receptor-related tyrosine kinase overactivation and its downstream JAK-STAT signaling, and subsequently kill LSCs or regulate LSCs biology remains largely unknown. To explore whether anlotinib could exert effective ani-LSCs activity, we treated LSC like cell lines (CD34+CD38-KG-1 and Kasumi-1) with anlotinib, and found anlotinib could effectively induce apoptosis of LSC-like cells in a dose- and time-dependent manner. Similar results were observed in primary CD34+CD38-AML LSCs; notably, anlotinib did not significantly kill normal CD34+ cells in vitro. Additionally, the anti-LSC activity of anlotinib was further confirmed in the xenograft mouse model by injection of Kasumi cells (LSC-like cell line) into irradiated female BALB/c nude mice. To determine whether anlotinib could inhibit the over activation of the GF receptor-related tyrosine kinase, we performed western blot at 12h after anlotinib treatment when LSC-like cells did not showed significant apoptosis. As a result, anlotinib inhibit c-kit phosphorylation and JAK2 activation. Intriguingly, unlike JAK2 inhibitors, anlotinib could not only the inhibit phosphorylation of STAT3 and STAT5 but also downregulate their expression. Chemoresistance and immune evasion were the key features of LSCs, JAK2-STAT3/5 signaling was reported to involved in chemoresistance by upregulating anti-apoptotic proteins such as Bcl-2 ,Mcl-1 and also involved in immune escape by inducing immune suppressive molecules such as PD-L1 ,TGF-β.Thus we evaluated Bcl-2 expression and found a significant decrease in LSC-likes cells after anlotinib treatment. Similarly, PD-L1 and TGF-β were also significantly downregulated after anlotinib treatment. In conclusion, anlotinib not only displayed the effective anti-LSCs activity but also might regulate the chemoresistance and immune evasion of LSC by downregulating the anti-apoptotic proteins and suppressive molecules such as PD-L1, TGF-β respectively. Consequently, anlotinib might has the potential to contribute to a deeper clearance of LSCs by combining with chemotherapy or immunotherapy. Disclosures No relevant conflicts of interest to declare.

Activation of pp60(src) is critical for stretch-induced orienting response in fibroblasts

1999 ◽  
Vol 112 (9) ◽  
pp. 1365-1373 ◽  
Author(s):  
X. Sai ◽  
K. Naruse ◽  
M. Sokabe
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Time Course ◽  
Kinase Inhibitor ◽  
Orienting Response ◽  
Cyclic Stretch ◽  
Wild Type ◽  
Herbimycin A ◽  
Molecular Masses

When subjected to uni-axial cyclic stretch (120% in length, 1 Hz), fibroblasts (3Y1) aligned perpendicular to the stretch axis in a couple of hours. Concomitantly with this orienting response, protein tyrosine phosphorylation of cellular proteins (molecular masses of approximately 70 kDa and 120–130 kDa) increased and peaked at 30 minutes. Immuno-precipitation experiments revealed that paxillin, pp125(FAK), and pp130(CAS) were included in the 70 kDa, and 120–130 kDa bands, respectively. Treatment of the cells with herbimycin A, a tyrosine kinase inhibitor, suppressed the stretch induced tyrosine phosphorylation and the orienting response suggesting that certain tyrosine kinases are activated by stretch. We focused on pp60(src), the most abundant tyrosine kinase in fibroblasts. The kinase activity of pp60(src) increased and peaked at 20 minutes after the onset of cyclic stretch. Treatment of the cells with an anti-sense S-oligodeoxynucleotide (S-ODN) against pp60(src), but not the sense S-ODN, inhibited the stretch induced tyrosine phosphorylation and the orienting response. To further confirm the involvement of pp60(src), we performed the same sets of experiments using c-src-transformed 3Y1 (c-src-3Y1) fibroblasts. Cyclic stretch induced a similar orienting response in c-src-3Y1 to that in wild-type 3Y1, but with a significantly faster rate. The time course of the stretch-induced tyrosine phosphorylation was also much faster in c-src-3Y1 than in 3Y1 fibroblasts. These results strongly suggest that cyclic stretch induces the activation of pp60(src) and that pp60(src) is indispensable for the tyrosine phosphorylation of pp130(CAS), pp125(FAK) and paxillin followed by the orienting response in 3Y1 fibroblasts.

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