scholarly journals Research Progress of the Functional Role of ACK1 in Breast Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-6
Author(s):  
Xia Liu ◽  
Xuan Wang ◽  
Lifang Li ◽  
Baolin Han
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinases ◽  
Structural Characteristics ◽  
Biological Behavior ◽  
Research Progress ◽  
Nonreceptor Tyrosine Kinase ◽  
Novel Therapeutic Strategies ◽  
Multiple Signaling ◽  
Nonreceptor Tyrosine Kinases

ACK1 is a nonreceptor tyrosine kinase with a unique structure, which is tightly related to the biological behavior of tumors. Previous studies have demonstrated that ACK1 was involved with multiple signaling pathways of tumor progression. Its crucial role in tumor cell proliferation, apoptosis, invasion, and metastasis was tightly related to the prognosis and clinicopathology of cancer. ACK1 has a unique way of regulating cellular pathways, different from other nonreceptor tyrosine kinases. As an oncogenic kinase, recent studies have shown that ACK1 plays a critical regulatory role in the initiation and progression of tumors. In this review, we will be summarizing the structural characteristics, activation, and regulation of ACK1 in breast cancer, aiming to deeply understand the functional and mechanistic role of ACK1 and provide novel therapeutic strategies for breast cancer treatment.

scholarly journals A novel nonreceptor tyrosine kinase, Srm: cloning and targeted disruption.

1994 ◽  
Vol 14 (10) ◽  
pp. 6915-6925 ◽  
Author(s):  
N Kohmura ◽  
T Yagi ◽  
Y Tomooka ◽  
M Oyanagi ◽  
R Kominami ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Structural Characteristics ◽  
Sequence Similarity ◽  
Embryonic Stem ◽  
Structural Features ◽  
Mutant Mice ◽  
Chromosome 2 ◽  
Nonreceptor Tyrosine Kinase ◽  
Nonreceptor Tyrosine Kinases

We have isolated a novel nonreceptor tyrosine kinase, Srm, that maps to the distal end of chromosome 2. It has SH2, SH2', and SH3 domains and a tyrosine residue for autophosphorylation in the kinase domain but lacks an N-terminal glycine for myristylation and a C-terminal tyrosine which, when phosphorylated, suppresses kinase activity. These are structural features of the recently identified Tec family of nonreceptor tyrosine kinases. The Srm N-terminal unique domain, however, lacks the structural characteristics of the Tec family kinases, and the sequence similarity is highest to Src in the SH region. The expression of two transcripts is rather ubiquitous and changes according to tissue and developmental stage. Mutant mice were generated by gene targeting in embryonic stem cells but displayed no apparent phenotype as in mutant mice expressing Src family kinases. These results suggest that Srm constitutes a new family of nonreceptor tyrosine kinases that may be redundant in function.

A novel nonreceptor tyrosine kinase, Srm: cloning and targeted disruption

1994 ◽  
Vol 14 (10) ◽  
pp. 6915-6925
Author(s):  
N Kohmura ◽  
T Yagi ◽  
Y Tomooka ◽  
M Oyanagi ◽  
R Kominami ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Structural Characteristics ◽  
Sequence Similarity ◽  
Embryonic Stem ◽  
Structural Features ◽  
Mutant Mice ◽  
Chromosome 2 ◽  
Nonreceptor Tyrosine Kinase ◽  
Nonreceptor Tyrosine Kinases

We have isolated a novel nonreceptor tyrosine kinase, Srm, that maps to the distal end of chromosome 2. It has SH2, SH2', and SH3 domains and a tyrosine residue for autophosphorylation in the kinase domain but lacks an N-terminal glycine for myristylation and a C-terminal tyrosine which, when phosphorylated, suppresses kinase activity. These are structural features of the recently identified Tec family of nonreceptor tyrosine kinases. The Srm N-terminal unique domain, however, lacks the structural characteristics of the Tec family kinases, and the sequence similarity is highest to Src in the SH region. The expression of two transcripts is rather ubiquitous and changes according to tissue and developmental stage. Mutant mice were generated by gene targeting in embryonic stem cells but displayed no apparent phenotype as in mutant mice expressing Src family kinases. These results suggest that Srm constitutes a new family of nonreceptor tyrosine kinases that may be redundant in function.

Role of PKC, tyrosine kinases, and Rho kinase in α-adrenoreceptor-mediated PASM contraction

2002 ◽  
Vol 283 (5) ◽  
pp. L1051-L1064 ◽  
Author(s):  
Derek S. Damron ◽  
Noriaki Kanaya ◽  
Yasuyuki Homma ◽  
Si-Oh Kim ◽  
Paul A. Murray
Keyword(s):  
Tyrosine Kinases ◽  
Rho Kinase ◽  
Isometric Tension ◽  
Vasomotor Tone ◽  
Tension Development ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle ◽  
Sensitizing Effect ◽  
Multiple Signaling

Our objectives were to identify the relative contributions of intracellular free Ca2+ concentration ([Ca2+]i) and myofilament Ca2+ sensitivity in the pulmonary artery smooth muscle (PASM) contractile response to the α-adrenoreceptor agonist phenylephrine (PE) and to assess the role of PKC, tyrosine kinases (TK), and Rho kinase (ROK) in that response. Our hypothesis was that multiple signaling pathways are involved in the regulation of [Ca2+]i, myofilament Ca2+sensitization, and vasomotor tone in response to α-adrenoreceptor stimulation of PASM. Simultaneous measurement of [Ca2+]i and isometric tension was performed in isolated canine pulmonary arterial strips loaded with fura 2-AM. PE-induced tension development was due to sarcolemmal Ca2+influx, Ca2+ release from inositol 1,4,5-trisphosphate-dependent sarcoplasmic reticulum Ca2+stores, and myofilament Ca2+ sensitization. Inhibition of either PKC or TK partially attenuated the sarcolemmal Ca2+influx component and the myofilament Ca2+ sensitizing effect of PE. Combined inhibition of PKC and TK did not have an additive attenuating effect on PE-induced Ca2+sensitization. ROK inhibition slightly decreased [Ca2+]i but completely inhibited myofilament Ca2+ sensitization. These results indicate that PKC and TK activation positively regulate sarcolemmal Ca2+ influx in response to α-adrenoreceptor stimulation in PASM but have relatively minor effects on myofilament Ca2+ sensitivity. ROK is the predominant pathway mediating PE-induced myofilament Ca2+sensitization.

scholarly journals Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 957 ◽  
Author(s):  
Milica Nedeljković ◽  
Ana Damjanović
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Chemotherapy Resistance ◽  
Standard Of Care ◽  
Drug Efflux ◽  
Molecular Signatures ◽  
Chemotherapy Treatment ◽  
Multiple Signaling

Triple-negative (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance. Accordingly, in recent years, tremendous effort has been made into elucidating the mechanisms of TNBC chemoresistance with the goal of identifying new molecular targets. It has become evident that the development of TNBC chemoresistance is multifaceted and based on the elaborate interplay of the tumor microenvironment, drug efflux, cancer stem cells, and bulk tumor cells. Alterations of multiple signaling pathways govern these interactions. Moreover, TNBC’s high heterogeneity, highlighted in the existence of several molecular signatures, presents a significant obstacle to successful treatment. In the present, in-depth review, we explore the contribution of key mechanisms to TNBC chemoresistance as well as emerging strategies to overcome them. We discuss novel anti-tumor agents that target the components of these mechanisms and pay special attention to their current clinical development while emphasizing the challenges still ahead of successful TNBC management. The evidence presented in this review outlines the role of crucial pathways in TNBC survival following chemotherapy treatment and highlights the importance of using combinatorial drug strategies and incorporating biomarkers in clinical studies.

scholarly journals Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation

2003 ◽  
Vol 23 (11) ◽  
pp. 3884-3896 ◽  
Author(s):  
Keith Q. Tanis ◽  
Darren Veach ◽  
Henry S. Duewel ◽  
William G. Bornmann ◽  
Anthony J. Koleske
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Intramolecular Interactions ◽  
Activation Loop ◽  
Additive Effects ◽  
Nonreceptor Tyrosine Kinase ◽  
Kinase Activation ◽  
Surface Receptors ◽  
Nonreceptor Tyrosine Kinases ◽  
Stimulation Of

ABSTRACT The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.

Cardioprotection involves activation of NF-κB via PKC-dependent tyrosine and serine phosphorylation of IκB-α

2003 ◽  
Vol 285 (4) ◽  
pp. H1753-H1758 ◽  
Author(s):  
Jun Zhang ◽  
Peipei Ping ◽  
Thomas M. Vondriska ◽  
Xian-Liang Tang ◽  
Guang-Wu Wang ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Coronary Occlusion ◽  
Kinase Inhibitor ◽  
Serine Phosphorylation ◽  
Inhibitory Protein ◽  
Nonreceptor Tyrosine Kinase ◽  
Pkc Inhibitor ◽  
Nonreceptor Tyrosine Kinases

Previous studies indicated that activation of PKC and Src tyrosine kinases by ischemic preconditioning (PC) may participate in the activation of NF-κB. However, the molecular mechanisms underlying activation of NF-κB during ischemic PC remain unknown. In the hearts of conscious rabbits, it was found that ischemic PC (6 cycles of 4-min coronary occlusion and 4-min reperfusion) significantly induced both tyrosine (+226.9 ± 42%) and serine (+137.0 ± 36%) phosphorylation of the NF-κB inhibitory protein IκB-α, concomitant with increased activation of the IκB-α kinases IKKα (+255.0 ± 46%) and IKKβ (+173.1 ± 35%). Furthermore, both tyrosine and serine phosphorylation of IκB-α were blocked by pretreatment with either the nonreceptor tyrosine kinase inhibitor lavendustin-A (LD-A) or the PKC inhibitor chelerythrine (Che) (both given at doses previously shown to block ischemic PC). Interestingly, Che completely abolished PC-induced activation of IKKα/β, whereas LD-A had no effect. In addition, IκB-α protein level did not change during ischemic PC. Together, these data indicate that ischemic PC-induced activation of NF-κB occurs through both tyrosine and serine phosphorylation of IκB-α and is regulated by nonreceptor tyrosine kinases and PKC.

Osmotic shrinkage elicits FAK- and Src phosphorylation and Src-dependent NKCC1 activation in NIH3T3 cells

2015 ◽  
Vol 308 (2) ◽  
pp. C101-C110 ◽  
Author(s):  
Line Jee Hartmann Rasmussen ◽  
Helene Steenkær Holm Müller ◽  
Bente Jørgensen ◽  
Stine Falsig Pedersen ◽  
Else Kay Hoffmann
Keyword(s):  
Focal Adhesion ◽  
Tyrosine Kinases ◽  
Volume Regulation ◽  
Mammalian Cells ◽  
Myosin Light Chain ◽  
Janus Kinase ◽  
Nih3t3 Cells ◽  
Src Inhibitor ◽  
Nonreceptor Tyrosine Kinases

The mechanisms linking cell volume sensing to volume regulation in mammalian cells remain incompletely understood. Here, we test the hypothesis that activation of nonreceptor tyrosine kinases Src, focal adhesion kinase (FAK), and Janus kinase-2 (Jak2) occurs after osmotic shrinkage of NIH3T3 fibroblasts and contributes to volume regulation by activation of NKCC1. FAK phosphorylation at Tyr397, Tyr576/577, and Tyr861 was increased rapidly after exposure to hypertonic (575 mOsm) saline, peaking after 10 (Tyr397, Tyr576/577) and 10–30 min (Tyr861). Shrinkage-induced Src family kinase autophosphorylation (pTyr416-Src) was induced after 2–10 min, and immunoprecipitation indicated that this reflected phosphorylation of Src itself, rather than Fyn and Yes. Phosphorylated Src and FAK partly colocalized with vinculin, a focal adhesion marker, after hypertonic shrinkage. The Src inhibitor pyrazolopyrimidine-2 (PP2, 10 μM) essentially abolished shrinkage-induced FAK phosphorylation at Tyr576/577 and Tyr861, yet not at Tyr397, and inhibited shrinkage-induced NKCC1 activity by ∼50%. The FAK inhibitor PF-573,228 augmented shrinkage-induced Src phosphorylation, and inhibited shrinkage-induced NKCC1 activity by ∼15%. The apparent role of Src in NKCC1 activation did not reflect phosphorylation of myosin light chain kinase (MLC), which was unaffected by shrinkage and by PP2, but may involve Jak2, a known target of Src, which was rapidly activated by osmotic shrinkage and inhibited by PP2. Collectively, our findings suggest a major role for Src and possibly the Jak2 axis in shrinkage-activation of NKCC1 in NIH3T3 cells, whereas no evidence was found for major roles for FAK and MLC in this process.

scholarly journals The Thrombopoietin Receptor Can Mediate Proliferation without Activation of the Jak-STAT Pathway

1997 ◽  
Vol 186 (12) ◽  
pp. 1947-1955 ◽  
Author(s):  
Marion Dorsch ◽  
Pang-Dian Fan ◽  
Nika N. Danial ◽  
Paul B. Rothman ◽  
Stephen P. Goff
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Signal Transducers ◽  
Thrombopoietin Receptor ◽  
Mitogen Activated Protein ◽  
Mutant Receptors ◽  
Nonreceptor Tyrosine Kinases ◽  
Stat Pathway

Cytokine receptors of the hematopoietic receptor superfamily lack intrinsic tyrosine kinase domains for the intracellular transmission of their signals. Instead all members of this family associate with Jak family nonreceptor tyrosine kinases. Upon ligand stimulation of the receptors, Jaks are activated to phosphorylate target substrates. These include STAT (signal transducers and activators of transcription) proteins, which after phosphorylation translocate to the nucleus and modulate gene expression. The exact role of the Jak-STAT pathway in conveying growth and differentiation signals remains unclear. Here we describe a deletion mutant of the thrombopoietin receptor (c-mpl) that has completely lost the capacity to activate Jaks and STATs but retains its ability to induce proliferation. This mutant still mediates TPO-induced phosphorylation of Shc, Vav, mitogen-activated protein kinase (MAPK) and Raf-1 as well as induction of c-fos and c-myc, although at somewhat reduced levels. Furthermore, we show that both wild-type and mutant receptors activate phosphatidylinositol (PI) 3-kinase upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is inhibited in the presence of the PI 3-kinase inhibitor wortmannin. These results demonstrate that the Jak-STAT pathway is dispensable for the generation of mitogenic signals by a cytokine receptor.

scholarly journals Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis

2002 ◽  
Vol 157 (3) ◽  
pp. 521-532 ◽  
Author(s):  
Philipp Niethammer ◽  
Markus Delling ◽  
Vladimir Sytnyk ◽  
Alexander Dityatev ◽  
Kiyoko Fukami ◽  
...  
Keyword(s):  
Neurite Outgrowth ◽  
Lipid Raft ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Fgf Receptor ◽  
Nonreceptor Tyrosine Kinase ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Neural Cell Adhesion ◽  
Nonreceptor Tyrosine Kinases

The neural cell adhesion molecule (NCAM) has been reported to stimulate neuritogenesis either via nonreceptor tyrosine kinases or fibroblast growth factor (FGF) receptor. Here we show that lipid raft association of NCAM is crucial for activation of the nonreceptor tyrosine kinase pathway and induction of neurite outgrowth. Transfection of hippocampal neurons of NCAM-deficient mice revealed that of the three major NCAM isoforms only NCAM140 can act as a homophilic receptor that induces neurite outgrowth. Disruption of NCAM140 raft association either by mutation of NCAM140 palmitoylation sites or by lipid raft destruction attenuates activation of the tyrosine focal adhesion kinase and extracellular signal–regulated kinase 1/2, completely blocking neurite outgrowth. Likewise, NCAM-triggered neurite outgrowth is also completely blocked by a specific FGF receptor inhibitor, indicating that cosignaling via raft-associated kinases and FGF receptor is essential for neuritogenesis.

scholarly journals PI3Kβ links integrin activation and PI(3,4)P2 production during invadopodial maturation

2019 ◽  
Vol 30 (18) ◽  
pp. 2367-2376 ◽  
Author(s):  
Zahra Erami ◽  
Samantha Heitz ◽  
Anne R. Bresnick ◽  
Jonathan M. Backer
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Breast Cancer Cells ◽  
Matrix Metalloproteases ◽  
Ph Domain ◽  
Integrin Activation ◽  
G Protein Coupled ◽  
Insight Into

The invasion of tumor cells from the primary tumor is mediated by invadopodia, actin-rich protrusive organelles that secrete matrix metalloproteases and degrade the extracellular matrix. This coupling between protrusive activity and matrix degradation facilitates tumor invasion. We previously reported that the PI3Kβ isoform of PI 3-kinase, which is regulated by both receptor tyrosine kinases and G protein–coupled receptors, is required for invasion and gelatin degradation in breast cancer cells. We have now defined the mechanism by which PI3Kβ regulates invadopodia. We find that PI3Kβ is specifically activated downstream from integrins, and is required for integrin-stimulated spreading and haptotaxis as well as integrin-stimulated invadopodia formation. Surprisingly, these integrin-stimulated and PI3Kβ-dependent responses require the production of PI(3,4)P2 by the phosphoinositide 5′-phosphatase SHIP2. Thus, integrin activation of PI3Kβ is coupled to the SHIP2-dependent production of PI(3,4)P2, which regulates the recruitment of PH domain-containing scaffolds such as lamellipodin to invadopodia. These findings provide novel mechanistic insight into the role of PI3Kβ in the regulation of invadopodia in breast cancer cells.

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