scholarly journals Regulation of Beclin 1-Mediated Autophagy by Oncogenic Tyrosine Kinases

2020 ◽  
Vol 21 (23) ◽  
pp. 9210
Author(s):  
Silvia Vega-Rubín-de-Celis ◽  
Lisa Kinch ◽  
Samuel Peña-Llopis
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Current Knowledge ◽  
Beclin 1 ◽  
Class Iii ◽  
Core Component ◽  
Post Translational Modifications ◽  
Autophagy Activity

Beclin 1 is a major regulator of autophagy, and it is a core component of the class III PI3K complexes. Beclin 1 is a highly conserved protein and its function is regulated in a number of ways, including post-translational modifications. Several studies indicate that receptor and non-receptor tyrosine kinases regulate autophagy activity in cancer, and some suggest the importance of Beclin 1 tyrosine phosphorylation in this process. Here we summarize the current knowledge of the mechanism whereby some oncogenic tyrosine kinases regulate autophagy through Beclin 1.

Casitas B-lineage lymphoma mutants activate AKT to induce transformation in cooperation with class III receptor tyrosine kinases

2013 ◽  
Vol 41 (3) ◽  
pp. 271-280.e4 ◽  
Author(s):  
Harald Polzer ◽  
Hanna Janke ◽  
Diana Schmid ◽  
Wolfgang Hiddemann ◽  
Karsten Spiekermann
Keyword(s):  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Class Iii ◽  
B Lineage

scholarly journals Novel Approaches to Target Mutant FLT3 Leukaemia

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2806
Author(s):  
Jörg P. Müller ◽  
Dirk Schmidt-Arras
Keyword(s):  
Tyrosine Kinases ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Class Iii ◽  
Poor Survival ◽  
Efficient Treatment ◽  
Oncogenic Mutations ◽  
Proliferation And Differentiation ◽  
Current Therapies ◽  
Novel Therapeutic Strategies

Fms-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinases (RTK) and is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene resulting in constitutively active FLT3 variants are frequently found in acute myeloid leukaemia (AML) patients and correlate with patient’s poor survival. Targeting FLT3 mutant leukaemic stem cells (LSC) is a key to efficient treatment of patients with relapsed/refractory AML. It is therefore essential to understand how LSC escape current therapies in order to develop novel therapeutic strategies. Here, we summarize the current knowledge on mechanisms of FLT3 activity regulation and its cellular consequences. Furthermore, we discuss how aberrant FLT3 signalling cooperates with other oncogenic lesions and the microenvironment to drive haematopoietic malignancies and how this can be harnessed for therapeutical purposes.

Activation of TrkA tyrosine kinase in embryonal carcinoma cells promotes cell compaction, independently of tyrosine phosphorylation of catenins

2000 ◽  
Vol 113 (9) ◽  
pp. 1601-1610
Author(s):  
M. Cozzolino ◽  
B. Giovannone ◽  
A. Serafino ◽  
K. Knudsen ◽  
A. Levi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Embryonal Carcinoma ◽  
Receptor Tyrosine Kinases ◽  
Mdck Cells ◽  
Current Evidence ◽  
Tyrosine Kinase Receptor ◽  
Beta Catenin

Cadherins are transmembrane receptors whose extracellular domain mediates homophilic cell-cell interactions, while their cytoplasmic domain associates with a family of proteins known as catenins. Although the mechanisms that regulate the assembly and functional state of cadherin-catenin complexes are poorly understood, current evidence supports a role for protein tyrosine kinase activity in regulating cell adhesion and migration. Tyrosine phosphorylation of catenins is thought to mediate loss of intercellular adhesion promoted by activation of receptor tyrosine kinases in epithelial cells. Here, we show that activation of ectopically expressed TrkA, the tyrosine kinase receptor for nerve growth factor (NGF), stimulates embryonal carcinoma P19 cells to develop extensive intercellular contacts and to assemble into closely packed clusters. Thus, activation of receptor tyrosine kinases can differentially regulate adhesiveness by cell-type-specific mechanisms. Furthermore, activation of TrkA in P19 and epithelial MDCK cells induces tyrosine phosphorylation of p120(ctn) and of beta-catenin, irrespective of the elicited cellular response. The selective Src tyrosine kinase inhibitor PP2, however, suppresses NGF- or HGF-induced tyrosine phosphorylation of catenins in both P19 and MDCK cells without interfering with the acquisition of a compacted or scattered phenotype. These findings provide a cogent argument for considering that tyrosine phosphorylation of catenins is dispensable for their interaction with cadherins and, ultimately, for the modulation of cadherin-based cell adhesion by receptor tyrosine kinases.

scholarly journals Modulation of the Kv1.3 Potassium Channel by Receptor Tyrosine Kinases

1997 ◽  
Vol 110 (5) ◽  
pp. 601-610 ◽  
Author(s):  
Mark R. Bowlby ◽  
Debra A. Fadool ◽  
Todd C. Holmes ◽  
Irwin B. Levitan
Keyword(s):  
Tyrosine Kinase ◽  
Potassium Channel ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Mutational Analysis ◽  
Inactivation Kinetics ◽  
Hek 293 ◽  
Voltage Dependent

The voltage-dependent potassium channel, Kv1.3, is modulated by the epidermal growth factor receptor (EGFr) and the insulin receptor tyrosine kinases. When the EGFr and Kv1.3 are coexpressed in HEK 293 cells, acute treatment of the cells with EGF during a patch recording can suppress the Kv1.3 current within tens of minutes. This effect appears to be due to tyrosine phosphorylation of the channel, as it is blocked by treatment with the tyrosine kinase inhibitor erbstatin, or by mutation of the tyrosine at channel amino acid position 479 to phenylalanine. Previous work has shown that there is a large increase in the tyrosine phosphorylation of Kv1.3 when it is coexpressed with the EGFr. Pretreatment of EGFr and Kv1.3 cotransfected cells with EGF before patch recording also results in a decrease in peak Kv1.3 current. Furthermore, pretreatment of cotransfected cells with an antibody to the EGFr ligand binding domain (α-EGFr), which blocks receptor dimerization and tyrosine kinase activation, blocks the EGFr-mediated suppression of Kv1.3 current. Insulin treatment during patch recording also causes an inhibition of Kv1.3 current after tens of minutes, while pretreatment for 18 h produces almost total suppression of current. In addition to depressing peak Kv1.3 current, EGF treatment produces a speeding of C-type inactivation, while pretreatment with the α-EGFr slows C-type inactivation. In contrast, insulin does not influence C-type inactivation kinetics. Mutational analysis indicates that the EGF-induced modulation of the inactivation rate occurs by a mechanism different from that of the EGF-induced decrease in peak current. Thus, receptor tyrosine kinases differentially modulate the current magnitude and kinetics of a voltage-dependent potassium channel.

scholarly journals Class III Receptor Tyrosine Kinases in Acute Leukemia – Biological Functions and Modern Laboratory Analysis

2015 ◽  
Vol 10s3 ◽  
pp. BMI.S22433 ◽  
Author(s):  
Rimma Berenstein
Keyword(s):  
Tyrosine Kinases ◽  
Complex Disease ◽  
Receptor Tyrosine Kinases ◽  
Physiological Role ◽  
Leukemic Cells ◽  
World Health ◽  
Laboratory Diagnostics ◽  
Screening Methods ◽  
Class Iii ◽  
Short Period

Acute myeloid leukemia (AML) is a complex disease caused by deregulation of multiple signaling pathways. Mutations in class III receptor tyrosine kinases (RTKs) have been implicated in alteration of cell signals concerning the growth and differentiation of leukemic cells. Point mutations, insertions, or deletions of RTKs as well as chromosomal translocations induce constitutive activation of the receptor, leading to uncontrolled proliferation of undifferentiated myeloid blasts. Aberrations can occur in all domains of RTKs causing either the ligand-independent activation or mimicking the activated conformation. The World Health Organization recommended including RTK mutations in the AML classification since their detection in routine laboratory diagnostics is a major factor for prognostic stratification of patients. Polymerase chain reaction (PCR)–based methods are well-validated for the detection of fms-related tyrosine kinase 3 ( FLT3) mutations and can easily be applied for other RTKs. However, when methodological limitations are reached, accessory techniques can be applied. For a higher resolution and more quantitative approach compared to agarose gel electrophoresis, PCR fragments can be separated by capillary electrophoresis. Furthermore, high-resolution melting and denaturing high-pressure liquid chromatography are reliable presequencing screening methods that reduce the sample amount for Sanger sequencing. Because traditional DNA sequencing is time-consuming, next-generation sequencing (NGS) is an innovative modern possibility to analyze a high amount of samples simultaneously in a short period of time. At present, standardized procedures for NGS are not established, but when this barrier is resolved, it will provide a new platform for rapid and reliable laboratory diagnostic of RTK mutations in patients with AML. In this article, the biological and physiological role of RTK mutations in AML as well as possible laboratory methods for their detection will be reviewed.

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