scholarly journals Alternative Splicing in Oncogenic Kinases: From Physiological Functions to Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Sabine Druillennec ◽  
Coralie Dorard ◽  
Alain Eychène
Keyword(s):  
Alternative Splicing ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Genetic Model ◽  
Physiological Functions ◽  
Model Studies ◽  
Eukaryotic Genes ◽  
Membrane Bound ◽  
Oncogenic Protein ◽  
Encoding Protein

Among the 518 protein kinases encoded by the human kinome, several of them act as oncoproteins in human cancers. Like other eukaryotic genes, oncogenes encoding protein kinases are frequently subjected to alternative splicing in coding as well as noncoding sequences. In the present paper, we will illustrate how alternative splicing can significantly impact on the physiological functions of oncogenic protein kinases, as demonstrated by mouse genetic model studies. This includes examples of membrane-bound tyrosine kinases receptors (FGFR2, Ret, TrkB, ErbB4, and VEGFR) as well as cytosolic protein kinases (B-Raf). We will further discuss how regular alternative splicing events of these kinases are in some instances implicated in oncogenic processes during tumor progression (FGFR, TrkB, ErbB2, Abl, and AuroraA). Finally, we will present typical examples of aberrant splicing responsible for the deregulation of oncogenic kinases activity in cancers (AuroraB, Jak2, Kit, Met, and Ron).

Protein Kinases Associated with Activation of Sickle Red Blood Cell Adhesion.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3567-3567
Author(s):  
Rahima Zennadi ◽  
Erin J. Whalen ◽  
Marilyn J. Telen
Keyword(s):  
Cell Adhesion ◽  
Adenylate Cyclase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinases ◽  
Regulatory Subunits ◽  
Protein Tyrosine ◽  
Cyclase Activation ◽  
Adenylate Cyclase Activation ◽  
Membrane Bound

Abstract We have previously found that activation of adenylate cyclase in sickle red cells (SS RBCs) results in increased RBC adhesion to cultured endothelial cells (EC) through activation of protein kinase A (PKA). Protein tyrosine phosphorylation by src family kinases, known to be present in normal RBCs, is also involved in enhancing SS RBC adhesion to EC, as inhibition of these kinases also inhibits activation of adhesion. However, in normal RBCs neither activation of adenylate cyclase nor cAMP analogs elicits a similar increase in cell adhesion. We therefore investigated whether normal and SS RBCs differed with respect to the protein kinases downstream of cAMP, such as PKA catalytic and regulatory subunits and protein tyrosine kinases p56lck, p56lyn and p72syk. We also investigated the extracellular signal regulated kinases p44 and p42 (ERK 1 and 2 respectively), which can be activated downstream of tyrosine kinases. PKA catalytic and regulatory subunits and ERK1/2 were studied after SS and normal RBCs were sham-treated or treated for 30 min with 80 μM forskolin, which activates adenylate cyclase. For protein tyrosine kinases, both SS and normal RBCs were sham-treated or treated with 1μg/ml Pertussis toxin, which suppresses Gαi-mediated inhibition of adenylate cyclase. Equal amounts of total membrane proteins were separated by polyacrylamide gel electrophoresis before transfer to nitrocellulose membrane. Protein kinases were detected in isolated membranes by immunoblotting using specific antibodies. Immunoblots showed that the levels of membrane-associated PKAcβ subunit were similar in both SS and normal RBCs and did not change after forskolin stimulation. However, treatment of SS RBCs with forskolin induced a significant reduction in membrane-bound PKARIIβ subunit. In general, dissociation of PKAR (regulatory) subunits is associated with activation of the catalytic (c) domain. In contrast, no change in the amount of membrane-bound PKARIIβ was observed when normal RBCs were treated with forskolin. These data demonstrate that PKARIIβ dissociated from PKAcβ after adenylate cyclase activation in SS RBCs, consistent with activation of PKAcβ. Our results thus suggest that activation of PKAcβ might be one of the mechanisms contributing to increased SS RBC adhesion. The amount of membrane-bound PKARIIα in SS RBCs did not change with stimulation, suggesting that PKAcα may not undergo activation as a result of forskolin stimulation. Immunoblots also showed no change in the levels of membrane-bound p56lck, p56lyn and p72syk detected before and after normal or SS RBCs were stimulated with Pertussis toxin. However, normal RBCs contained lower levels of protein tyrosine kinases, including p56lyn, p56lck and p76syk. We also found that ERK1/2 are bound to the membrane in normal and SS RBCs. The total amount of membrane-associated ERK1 (p44) is markedly higher in SS RBCs than in normal RBCs, and membrane ERK1 levels increased only in SS RBCs after stimulation with forskolin. Taken together, our results suggest that PKAcβ is activated in SS RBCs but not in normal RBCs in response to elevation of cAMP. The higher levels of src kinases in SS RBCs may also contribute to an increased adhesive response to adenylate cyclase activation compared to normal RBCs. In addition, we have obtained the first evidence that ERK1/2 is conserved in enucleated human erythrocytes and that ERK1 is recruited to bind to SS RBC membranes as a result of adenylate cyclase activation, suggesting that it might be involved in regulating cell adhesion.

scholarly journals Enhanced Transcriptomic Resilience following Increased Alternative Splicing and Differential Isoform Production between Air Pollution Conurbations

Atmosphere ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 959
Author(s):  
Shengkai Pan ◽  
Xiaokai Feng ◽  
Daniel Pass ◽  
Rachel A. Adams ◽  
Yusong Wang ◽  
...  
Keyword(s):  
Air Pollution ◽  
Alternative Splicing ◽  
Real Life ◽  
Chronic Obstructive ◽  
Translational Efficiency ◽  
Ambient Particulate Matter ◽  
Obstructive Pulmonary Disease ◽  
Adverse Health Outcomes ◽  
Membrane Bound ◽  
Migration Capacity

Adverse health outcomes caused by ambient particulate matter (PM) pollution occur in a progressive process, with neutrophils eliciting inflammation or pathogenesis. We investigated the toxico-transcriptomic mechanisms of PM in real-life settings by comparing healthy residents living in Beijing and Chengde, the opposing ends of a well-recognised air pollution (AP) corridor in China. Beijing recruits (BRs) uniquely expressed ~12,000 alternative splicing (AS)-derived transcripts, largely elevating the proportion of transcripts significantly correlated with PM concentration. BRs expressed PM-associated isoforms (PMAIs) of PFKFB3 and LDHA, encoding enzymes responsible for stimulating and maintaining glycolysis. PMAIs of PFKFB3 featured different COOH-terminals, targeting PFKFB3 to different sub-cellular functional compartments and stimulating glycolysis. PMAIs of LDHA have longer 3′UTRs relative to those expressed in Chengde recruits (CRs), allowing glycolysis maintenance by enhancing LDHA mRNA stability and translational efficiency. PMAIs were directly regulated by different HIF-1A and HIF-1B isoforms. BRs expressed more non-functional Fas isoforms, and a resultant reduction of intact Fas proportion is expected to inhibit the transmission of apoptotic signals and prolong neutrophil lifespan. BRs expressed both membrane-bound and soluble IL-6R isoforms instead of only one in CRs. The presence of both IL-6R isoforms suggested a higher migration capacity of neutrophils in BRs. PMAIs of HIF-1A and PFKFB3 were downregulated in Chronic Obstructive Pulmonary Disease patients compared with BRs, implying HIF-1 mediated defective glycolysis may mediate neutrophil dysfunction. PMAIs could explain large variances of different phenotypes, highlighting their potential application as biomarkers and therapeutic targets in PM-induced diseases, which remain poorly elucidated.

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.

Role of protein kinases in regulating sheep erythrocyte K-Cl cotransport

1996 ◽  
Vol 271 (1) ◽  
pp. C255-C263 ◽  
Author(s):  
P. W. Flatman ◽  
N. C. Adragna ◽  
P. K. Lauf
Keyword(s):  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Sheep Erythrocyte ◽  
Inhibition Constant ◽  
Calyculin A ◽  
Sheep Erythrocytes ◽  
A 23187 ◽  
Maximal Activation

K-Cl cotransport in sheep erythrocytes can be activated by treatment either with A-23187 and EDTA to reduce concentration of internal ionized Mg [Mg]i) to submicromolar levels, with staurosporine, a potent kinase inhibitor, or with N-ethylmaleimide (NEM). Activation by these maneuvers is prevented and reversed by genistein [inhibition constant (Ki) of 15 microM], which inhibits tyrosine kinases (TK). The related glycosidated compound genistin, which does not inhibit TK, does not inhibit transport, whereas another TK inhibitor, tyrphostin B46, inhibits both basal and stimulated transport (Ki of 28 microM). Cotransport activation by NEM is prevented and reversed by the phosphatase inhibitor, calyculin A, and activation by staurosporine occurs only if cells contain ATP. Increasing [Mg]i inhibits cotransport in the presence of calyculin A whether or not staurosporine is present as well. Our work suggests that genistein inhibits cotransport through a TK and that staurosporine and NEM activate cotransport, probably through inhibition of other kinases, causing stimulation through dephosphorylation of a protein (possibly the transporter itself) be a serine/threonine phosphatase. [Mg]i inhibits cotransport by activating a kinase (concentration for half-maximal activation of 10 microM) that phosphorylates this protein.

scholarly journals The full-length transcriptome of Spartina alterniflora reveals the complexity of high salt tolerance in monocotyledonous halophyte

2019 ◽  
Author(s):  
Wenbin Ye ◽  
Taotao Wang ◽  
Wei Wei ◽  
Shuaitong Lou ◽  
Faxiu Lan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Salt Stress ◽  
Alternative Splicing ◽  
Salt Tolerance ◽  
Protein Kinases ◽  
Spartina Alterniflora ◽  
High Salt ◽  
Full Length ◽  
Salt Tolerant ◽  
High Salt Tolerance

ABSTRACTSpartina alterniflora (Spartina) is the only halophyte in the salt marsh. However, the molecular basis of its high salt tolerance remains elusive. In this study, we used PacBio full-length single molecule long-read sequencing and RNA-seq to elucidate the transcriptome dynamics of high salt tolerance in Spartina by salt-gradient experiments (0, 350, 500 and 800 mM NaCl). We systematically analyzed the gene expression diversity and deciphered possible roles of ion transporters, protein kinases and photosynthesis in salt tolerance. Moreover, the co-expression network analysis revealed several hub genes in salt stress regulatory networks, including protein kinases such as SaOST1, SaCIPK10 and three SaLRRs. Furthermore, high salt stress affected the gene expression of photosynthesis through down-regulation at the transcription level and alternative splicing at the post-transcriptional level. In addition, overexpression of two Spartina salt-tolerant genes SaHSP70-I and SaAF2 in Arabidopsis significantly promoted the salt tolerance of transgenic lines. Finally, we built the SAPacBio website for visualizing the full-length transcriptome sequences, transcription factors, ncRNAs, salt-tolerant genes, and alternative splicing events in Spartina. Overall, this study sheds light on the high salt tolerance mechanisms of monocotyledonous-halophyte and demonstrates the potential of Spartina genes for engineering salt-tolerant plants.

scholarly journals Fibroblast Growth Factor Receptor-Mediated Rescue of x-Ephrin B1-Induced Cell Dissociation in XenopusEmbryos

2000 ◽  
Vol 20 (2) ◽  
pp. 724-734 ◽  
Author(s):  
Lisa D. Chong ◽  
Eui Kyun Park ◽  
Erin Latimer ◽  
Robert Friesel ◽  
Ira O. Daar
Keyword(s):  
Cell Adhesion ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Fgf Receptor ◽  
Cell Adhesion And Migration ◽  
Membrane Bound ◽  
And Migration

ABSTRACT The Eph family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. Genetic evidence suggests that ephrins may transduce signals and become tyrosine phosphorylated during embryogenesis. However, the induction and functional significance of ephrin phosphorylation is not yet clear. Here, we report that when we used ectopically expressed proteins, we found that an activated fibroblast growth factor (FGF) receptor associated with and induced the phosphorylation of ephrin B1 on tyrosine. Moreover, this phosphorylation reduced the ability of overexpressed ephrin B1 to reduce cell adhesion. In addition, we identified a region in the cytoplasmic tail of ephrin B1 that is critical for interaction with the FGF receptor; we also report FGF-induced phosphorylation of ephrins in a neural tissue. This is the first demonstration of communication between the FGF receptor family and the Eph ligand family and implicates cross talk between these two cell surface molecules in regulating cell adhesion.

scholarly journals Vasodilation induced by oxygen/glucose deprivation is attenuated in cerebral arteries of SUR2 null mice

2011 ◽  
Vol 301 (4) ◽  
pp. H1360-H1368 ◽  
Author(s):  
Adebowale Adebiyi ◽  
Elizabeth M. McNally ◽  
Jonathan H. Jaggar
Keyword(s):  
Smooth Muscle ◽  
Genetic Model ◽  
Cerebral Arteries ◽  
Glucose Deprivation ◽  
Metabolic Inhibition ◽  
Myogenic Tone ◽  
Partial Recovery ◽  
Sulfonylurea Receptor ◽  
Physiological Functions ◽  
Mitochondrial Atp Synthase

Physiological functions of arterial smooth muscle cell ATP-sensitive K+ (KATP) channels, which are composed of inwardly rectifying K+ channel 6.1 and sulfonylurea receptor (SUR)-2 subunits, during metabolic inhibition are unresolved. In the present study, we used a genetic model to investigate the physiological functions of SUR2-containing KATP channels in mediating vasodilation to hypoxia, oxygen and glucose deprivation (OGD) or metabolic inhibition, and functional recovery following these insults. Data indicate that SUR2B is the only SUR isoform expressed in murine cerebral artery smooth muscle cells. Pressurized SUR2 wild-type (SUR2wt) and SUR2 null (SUR2nl) mouse cerebral arteries developed similar levels of myogenic tone and dilated similarly to hypoxia (<10 mmHg Po2). In contrast, vasodilation induced by pinacidil, a KATP channel opener, was ∼71% smaller in SUR2nl arteries. Human cerebral arteries also expressed SUR2B, developed myogenic tone, and dilated in response to hypoxia and pinacidil. OGD, oligomycin B (a mitochondrial ATP synthase blocker), and CCCP (a mitochondrial uncoupler) all induced vasodilations that were ∼39–61% smaller in SUR2nl than in SUR2wt arteries. The restoration of oxygen and glucose following OGD or removal of oligomycin B and CCCP resulted in partial recovery of tone in both SUR2wt and SUR2nl cerebral arteries. However, SURnl arteries regained ∼60–82% more tone than did SUR2wt arteries. These data indicate that SUR2-containing KATP channels are functional molecular targets for OGD, but not hypoxic, vasodilation in cerebral arteries. In addition, OGD activation of SUR2-containing KATP channels may contribute to postischemic loss of myogenic tone.

scholarly journals Identification of a Fungi-Specific Lineage of Protein Kinases Closely Related to Tyrosine Kinases

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89813 ◽  
Author(s):  
Zhongtao Zhao ◽  
Qiaojun Jin ◽  
Jin-Rong Xu ◽  
Huiquan Liu
Keyword(s):  
Protein Kinases ◽  
Tyrosine Kinases
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