Beyond calcium: new signaling pathways for Tec family kinases

2002 ◽  
Vol 115 (15) ◽  
pp. 3039-3048 ◽  
Author(s):  
Aya Takesono ◽  
Lisa D. Finkelstein ◽  
Pamela L. Schwartzberg
Keyword(s):  
Signaling Pathways ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Receptor Tyrosine Kinases ◽  
Cellular Transformation ◽  
Antigen Receptors ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Tec Kinases ◽  
Wide Range

The Tec kinases represent the second largest family of mammalian non-receptor tyrosine kinases and are distinguished by the presence of distinct proline-rich regions and pleckstrin homology domains that are required for proper regulation and activation. Best studied in lymphocyte and mast cells, these kinases are critical for the full activation of phospholipase-C γ (PLC-γ) and Ca2+ mobilization downstream of antigen receptors. However, it has become increasingly clear that these kinases are activated downstream of many cell-surface receptors,including receptor tyrosine kinases, cytokine receptors, integrins and G-protein-coupled receptors. Evidence suggests that the Tec kinases influence a wide range of signaling pathways controlling activation of MAP kinases,actin reorganization, transcriptional regulation, cell survival and cellular transformation. Their impact on cellular physiology suggests that the Tec kinases help regulate multiple cellular processes beyond Ca2+mobilization.

scholarly journals Proteolytic Cleavage of Receptor Tyrosine Kinases

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 660
Author(s):  
Hao Huang
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Large Family ◽  
Proteolytic Cleavage ◽  
Signal Transduction Pathways ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Rtk Signaling ◽  
Essential Components ◽  
Multiple Receptor

The receptor tyrosine kinases (RTKs) are a large family of cell-surface receptors, which are essential components of signal transduction pathways. There are more than fifty human RTKs that can be grouped into multiple RTK subfamilies. RTKs mediate cellular signaling transduction, and they play important roles in the regulation of numerous cellular processes. The dysregulation of RTK signaling is related to various human diseases, including cancers. The proteolytic cleavage phenomenon has frequently been found among multiple receptor tyrosine kinases. More and more information about proteolytic cleavage in RTKs has been discovered, providing rich insight. In this review, we summarize research about different aspects of RTK cleavage, including its relation to cancer, to better elucidate this phenomenon. This review also presents proteolytic cleavage in various members of the RTKs.

scholarly journals Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 513 ◽  
Author(s):  
Marina Leite ◽  
Miguel S. Marques ◽  
Joana Melo ◽  
Marta T. Pinto ◽  
Bruno Cavadas ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Receptor Activation ◽  
Degradation Pathway ◽  
Mrna Levels ◽  
H Pylori

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.

scholarly journals Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Sareshma Sudhesh Dev ◽  
Syafiq Asnawi Zainal Abidin ◽  
Reyhaneh Farghadani ◽  
Iekhsan Othman ◽  
Rakesh Naidu
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Surface Proteins ◽  
Downstream Signaling ◽  
Anti Cancer ◽  
Rtk Inhibitors

Receptor tyrosine kinases (RTKs) are transmembrane cell-surface proteins that act as signal transducers. They regulate essential cellular processes like proliferation, apoptosis, differentiation and metabolism. RTK alteration occurs in a broad spectrum of cancers, emphasising its crucial role in cancer progression and as a suitable therapeutic target. The use of small molecule RTK inhibitors however, has been crippled by the emergence of resistance, highlighting the need for a pleiotropic anti-cancer agent that can replace or be used in combination with existing pharmacological agents to enhance treatment efficacy. Curcumin is an attractive therapeutic agent mainly due to its potent anti-cancer effects, extensive range of targets and minimal toxicity. Out of the numerous documented targets of curcumin, RTKs appear to be one of the main nodes of curcumin-mediated inhibition. Many studies have found that curcumin influences RTK activation and their downstream signaling pathways resulting in increased apoptosis, decreased proliferation and decreased migration in cancer both in vitro and in vivo. This review focused on how curcumin exhibits anti-cancer effects through inhibition of RTKs and downstream signaling pathways like the MAPK, PI3K/Akt, JAK/STAT, and NF-κB pathways. Combination studies of curcumin and RTK inhibitors were also analysed with emphasis on their common molecular targets.

scholarly journals SRC Kinase in Glioblastoma: News from an Old Acquaintance

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1558 ◽  
Author(s):  
Claudia Cirotti ◽  
Claudia Contadini ◽  
Daniela Barilà
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Metabolic Reprogramming ◽  
Constitutive Activity ◽  
Therapeutic Approaches ◽  
Resistance To Therapy ◽  
Downstream Signaling ◽  
Wide Range ◽  
Therapy Effectiveness

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.

scholarly journals A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcγ Receptors on Macrophages

1997 ◽  
Vol 186 (7) ◽  
pp. 1027-1039 ◽  
Author(s):  
Mary T. Crowley ◽  
Patrick S. Costello ◽  
Cheryl J. Fitzer-Attas ◽  
Martin Turner ◽  
Fanying Meng ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Tyrosine Kinases ◽  
Map Kinases ◽  
Critical Role ◽  
Antigen Receptors ◽  
Phosphatidylinositol 3 Kinase ◽  
Kinase Activation ◽  
Latex Beads ◽  
Signaling Events ◽  
Escherichia Coli Bacteria

Receptors on macrophages for the Fc region of IgG (FcγR) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcγR cross-linking. Macrophages derived from Syk-deficient (Syk−) mice were defective in phagocytosis of particles bound by FcγRs, as well as in many FcγR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk− macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk− macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcγRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcγR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcγR-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon FcγR engagement, accompanied by a delay in FcγR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcγR-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by FcγR's analogous to models of signaling by the B and T cell antigen receptors.

scholarly journals Receptor tyrosine kinases regulate signal transduction through a liquid–liquid phase separated state

2019 ◽  
Author(s):  
Chi-Chuan Lin ◽  
Kin Man Suen ◽  
Polly-Anne Jeffrey ◽  
Lukasz Wieteska ◽  
Amy Stainthorp ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Liquid Phase ◽  
Tyrosine Kinases ◽  
Molecular Diffusion ◽  
Receptor Tyrosine Kinases ◽  
Sh2 Domain ◽  
Effector Proteins ◽  
Downstream Effector ◽  
Downstream Effectors ◽  
Wide Range

Receptor tyrosine kinases (RTKs), the largest class of transmembrane cell surface receptors, initiate signalling pathways which regulate diverse cellular processes. On activation these receptors rapidly recruit multiple downstream effector proteins to moderate affinity tyrosyl phosphate (pY) binding sites. However, the mechanism for expedient downstream effector protein recruitment via random molecular diffusion through the cytoplasm is not fully understood. One way in which the probabilistic outcome associated with random diffusion could be alleviated is through localized accumulation of high effective concentrations of signalling proteins in discrete pools in the cell (1). The inclusion of interacting proteins into liquid-liquid phase-separated (LLPS), membraneless protein droplets maintains functionally relevant proteins at high concentrations in a liquid phase at the required point of action, enhancing equilibrium binding and enzyme activity (2–6). These LLPS states have been associated with a wide range of cellular functions including regulation of signalling through, for example, nephrin (7, 8), the T-cell receptor (9), mTOR (10), and Sos-Ras (11), however, whether LLPS extends to RTK-mediated signal transduction has not been investigated. Here, we show that an RTK, fibroblast growth factor receptor 2 (FGFR2), forms a signalling competent LLPS state with two downstream effectors, a tandem Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (Shp2), and 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma 1 (Plcγ1). We show that these proteins assemble into a ternary complex which exploits LLPS condensation to simultaneously modulate kinase, phosphatase and phospholipase activities. Therefore, LLPS formation ensures that the requirement for prolonged, high-fidelity signalling is achieved. Additional RTKs also form LLPS with their downstream effectors, suggesting that formation of biological condensates is a key organising principle of RTK-mediated signalling, with broad implications for further mechanistic studies as well as therapeutic intervention.

Tyrosine 842 Residue in the Activation Loop of FLT3-ITD Is Indespensible for Oncogenic Transformation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1561-1561
Author(s):  
Julhash U. Kazi ◽  
Lars Rönnstrand
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Conflicts Of Interest ◽  
Point Mutations ◽  
Cellular Transformation ◽  
Receptor Activation ◽  
Tumor Formation ◽  
Activation Loop ◽  
Tyrosine Residues

Abstract The receptor tyrosine kinase FLT3 is mutated in around 30% of acute myeloid leukemia patients. The so-called internal tandem duplication (ITD) mutation in the juxtamembrane domain is the most common type of mutation in FLT3. Other oncogenic mutations include point mutations in the kinase domain. One of the hallmark of receptor activation is phosphorylation on several tyrosine residues in the receptor. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. The tyrosine residue Y842, which is located in the activation loop of FLT3, and is well conserved in all receptor tyrosine kinases. It has been demonstrated that tyrosine phosphorylation of the activation loop is essential for the activity of some but not all receptor tyrosine kinases. In this report we show that phosphorylation on Y842 residue is dispensable for receptor activity and stability. However, Y842 plays critical roles in oncogenic FLT3-ITD mediated transformation. We have shown that a Y-to-F mutation (Y842F) results in reduced cell viability and proliferation. This mutation also led to dramatic decrease in in vitro colony formation in semi-solid medium. Furthermore, cells carrying the Y842F mutant of FLT3-ITD displayed significant delay in tumor formation in nude mice. Gene expression analysis, using microarrays, showed that mutation of Y842 causes suppression of anti-apoptotic genes. Finally, we showed that phosphorylated Y842 is a binding site for SHP2 and mutation of this site results in impaired activation of signaling through the RAS/ERK pathway. Collectively, our data suggest that Y842 in FLT3 plays an important role in FLT3-mediated RAS/ERK signaling and cellular transformation. Disclosures No relevant conflicts of interest to declare.

Bidirectional signaling of ErbB and Eph receptors at synapses

2008 ◽  
Vol 4 (3) ◽  
pp. 211-221 ◽  
Author(s):  
Yu Chen ◽  
Amy K.Y. Fu ◽  
Nancy Y. Ip
Keyword(s):  
Neural Development ◽  
Tyrosine Kinases ◽  
Synapse Formation ◽  
Receptor Tyrosine Kinases ◽  
Eph Receptors ◽  
Surface Receptors ◽  
Reverse Signaling ◽  
Synaptic Functions ◽  
Bidirectional Signaling ◽  
Spine Morphogenesis

Synapse development and remodeling are regulated by a plethora of molecules such as receptor tyrosine kinases (RTKs), a family of cell surface receptors that play critical roles in neural development. Two families of RTKs implicated in synaptic functions, ErbBs and Ephs, share similar characteristics in terms of exhibiting forward and reverse signaling. In this review, we will discuss the latest advances in the functions of ErbBs and Ephs at the synapse, including dendritic spine morphogenesis, synapse formation and maturation, and synaptic transmission and plasticity. In addition to signaling at interneuronal synapses, communication between neuron and glia is increasingly implicated in the control of synaptic functions. Studies on RTKs and their cognate ligands in glial cells enhance our understanding on the nature of ‘tripartite synapse’. Implications of these signaling events in human diseases will be discussed.

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