scholarly journals Analysis of Protein Kinase Domain and Tyrosine Kinase or Serine/Threonine Kinase signatures Involved In Lung Cancer

2014 ◽  
Author(s):  
Manas Ranjan Barik ◽  
Tripti Kaur Bagga ◽  
Anupam Bhattacharya ◽  
Bhagath Kumar Palaka ◽  
Kasi Viswanath Kotapati ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Phylogenetic Tree ◽  
Protein Kinases ◽  
Kinase Domain ◽  
Activation Process ◽  
Serine Threonine Kinase ◽  
Protein Kinase Domain ◽  
Threonine Kinase ◽  
Genetic Components

Lung cancer results when normal check and balance system of cell division is disrupted and ultimately the cells divide and proliferate in an uncontrollable manner forming a mass of cells in our body, known as tumor. Frequent mutations in Protein Kinase Domain alter the process of phosphorylation which results in abnormality in regulations of cell apoptosis and differentiation. Tyrosine Protein kinases and Serine/Threonine Protein Kinases are the two broad classes of protein kinases in accordance to their substrate specificity. The study of Tyrosine protein kinase and serine Kinase coding regions have the importance of sequence and structure determinants of cancer-causing mutations from mutation-dependent activation process. In the present study, we analyzed huge amounts of data extracted from various biological databases and NCBI. Out of the 534 proteins that may play a role in lung cancer, 71 proteins were selected that are likely to be actively involved in lung cancer. These proteins were evaluated by employing Multiple Sequence Alignment and a Phylogenetic tree was constructed using Neighbor-Joining Algorithm. From the constructed phylogenetic tree, protein kinase domain and motif study was performed. The results of this study revealed that the presence of Protein Kinase Domain and Tyrosine or Serine/Threonine Kinase signatures in some of the proteins are mutated, which play a dominant role in the pathogenesis of Lung Cancer and these may be addressed with the help of inhibitors to develop an efficient anticancer drugs. Furthermore, the present study contributes to the possibility that genetic components are more important in Lung Cancer as compared to environmental and smoking(carcinogens) factors.

scholarly journals Analysis of Protein Kinase Domain and Tyrosine Kinase or Serine/Threonine Kinase signatures Involved In Lung Cancer

2014 ◽  
Author(s):  
Manas Ranjan Barik ◽  
Tripti Kaur Bagga ◽  
Anupam Bhattacharya ◽  
Bhagath Kumar Palaka ◽  
Kasi Viswanath Kotapati ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Phylogenetic Tree ◽  
Protein Kinases ◽  
Kinase Domain ◽  
Activation Process ◽  
Serine Threonine Kinase ◽  
Protein Kinase Domain ◽  
Threonine Kinase ◽  
Genetic Components

Lung cancer results when normal check and balance system of cell division is disrupted and ultimately the cells divide and proliferate in an uncontrollable manner forming a mass of cells in our body, known as tumor. Frequent mutations in Protein Kinase Domain alter the process of phosphorylation which results in abnormality in regulations of cell apoptosis and differentiation. Tyrosine Protein kinases and Serine/Threonine Protein Kinases are the two broad classes of protein kinases in accordance to their substrate specificity. The study of Tyrosine protein kinase and serine Kinase coding regions have the importance of sequence and structure determinants of cancer-causing mutations from mutation-dependent activation process. In the present study, we analyzed huge amounts of data extracted from various biological databases and NCBI. Out of the 534 proteins that may play a role in lung cancer, 71 proteins were selected that are likely to be actively involved in lung cancer. These proteins were evaluated by employing Multiple Sequence Alignment and a Phylogenetic tree was constructed using Neighbor-Joining Algorithm. From the constructed phylogenetic tree, protein kinase domain and motif study was performed. The results of this study revealed that the presence of Protein Kinase Domain and Tyrosine or Serine/Threonine Kinase signatures in some of the proteins are mutated, which play a dominant role in the pathogenesis of Lung Cancer and these may be addressed with the help of inhibitors to develop an efficient anticancer drugs. Furthermore, the present study contributes to the possibility that genetic components are more important in Lung Cancer as compared to environmental and smoking(carcinogens) factors.

scholarly journals Membrane localization of the kinase which phosphorylates p34cdc2 on threonine 14.

1994 ◽  
Vol 5 (3) ◽  
pp. 273-282 ◽  
Author(s):  
S Kornbluth ◽  
B Sebastian ◽  
T Hunter ◽  
J Newport
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Schizosaccharomyces Pombe ◽  
Protein Kinases ◽  
Membrane Fraction ◽  
Kinase Activity ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Dual Specificity ◽  
Detergent Extraction

The key regulator of entry into mitosis is the serine/threonine kinase p34cdc2. This kinase is regulated both by association with cyclins and by phosphorylation at several sites. Phosphorylation at Tyr 15 and Thr 14 are believed to inhibit the kinase activity of cdc2. In Schizosaccharomyces pombe, the wee1 (and possibly mik1) protein kinase catalyzes phosphorylation of Tyr 15. It is not clear whether these or other, as yet unidentified, protein kinases phosphorylate Thr 14. In this report we show, using extracts of Xenopus eggs, that the Thr 14-directed kinase is tightly membrane associated. Specifically, we have shown that a purified membrane fraction, in the absence of cytoplasm, can promote phosphorylation of cdc2 on both Thr 14 and Tyr 15. In contrast, the cytoplasm can phosphorylate cdc2 only on Tyr 15, suggesting the existence of at least two distinctly localized subpopulations of cdc2 Tyr 15-directed kinases. The membrane-associated Tyr 15 and Thr 14 kinase activities behaved similarly during salt or detergent extraction and were similarly regulated during the cell cycle and by the checkpoint machinery that delays mitosis while DNA is being replicated. This suggests the possibility that a dual-specificity membrane-associated protein kinase may catalyze phosphorylation of both Tyr 15 and Thr 14.

scholarly journals A promiscuous kinase inhibitor delineates the conspicuous structural features of protein kinase CK2a1

2019 ◽  
Vol 75 (7) ◽  
pp. 515-519
Author(s):  
Masato Tsuyuguchi ◽  
Tetsuko Nakaniwa ◽  
Masaaki Sawa ◽  
Isao Nakanishi ◽  
Takayoshi Kinoshita
Keyword(s):  
Crystal Structure ◽  
Protein Kinase ◽  
Crystal Structures ◽  
Crucial Role ◽  
Kinase Inhibitor ◽  
Structural Features ◽  
Kinase Domain ◽  
Selective Inhibitors ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

Protein kinase CK2a1 is a serine/threonine kinase that plays a crucial role in the growth, proliferation and survival of cells and is a well known target for tumour and glomerulonephritis therapies. Here, the crystal structure of the kinase domain of CK2a1 complexed with 5-iodotubercidin (5IOD), an ATP-mimetic inhibitor, was determined at 1.78 Å resolution. The structure shows distinct structural features and, in combination with a comparison of the crystal structures of five off-target kinases complexed with 5IOD, provides valuable information for the development of highly selective inhibitors.

Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer

2008 ◽  
Vol 26 (7) ◽  
pp. 1135-1141 ◽  
Author(s):  
Yun Oh ◽  
Roy S. Herbst ◽  
Howard Burris ◽  
Ann Cleverly ◽  
Luna Musib ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Small Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Stage Iv ◽  
Small Cell ◽  
Small Cell Lung ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Grade 3

PurposeEnzastaurin, an oral serine/threonine kinase inhibitor, suppresses protein kinase C (PKC) and protein kinase B/AK transforming (AKT) signaling, induces tumor cell apoptosis, and inhibits proliferation and angiogenesis. Increased PKC and AKT activity is associated with poor prognosis in non–small-cell lung cancer (NSCLC). This phase II trial of enzastaurin was conducted to determine the 6-month progression-free survival (PFS) rate in advanced, metastatic NSCLC.Patients and MethodsPatients with metastatic (stage IV and wet IIIB) NSCLC, Eastern Cooperative Oncology Group performance status ≤ 2, and ≤ two prior systemic regimens (including one or more platinum-based chemotherapy regimens) received 500 mg of enzastaurin administered once daily.ResultsFifty-five patients were enrolled (55% male patients, 45% female patients; median age, 63 years; range, 44 to 82 years; 78% of patients having stage IV disease). Adenocarcinoma was the most common diagnosis (65%). Prior therapies included radiotherapy (73%) and epidermal growth factor inhibitors (29%). Median PFS was 1.8 months (95% CI, 1.7 to 1.9). Six-month PFS rate was 13% (95% CI, 3.9% to 21.5%). Median overall survival (OS) was 8.4 months (95% CI, 6.0 to 13.6 months). The 12-month OS rate was 44% (95% CI, 30.5% to 57.3%). Nineteen patients (35%) had stable disease. No objective responses were observed. Seven patients (13%) had PFS ≥ 6 months, three of whom continued for more than 10 months. The most common toxicity was fatigue (grade ≤ 3; n = 17). Grade 3 or worse toxicities were fatigue (n = 2), thromboembolism (n = 1), ataxia (n = 1), and anemia (n = 1). Two patients discontinued treatment because of drug-related fatigue and dizziness. Five patients died while enrolled in the study (non drug-related).ConclusionAlthough the primary end point of a 20% PFS rate was not achieved, 13% of the patients had PFS for ≥ 6 months. Given the tolerability and survival data, evaluation of enzastaurin in combination with cytotoxic drugs is warranted in NSCLC.

scholarly journals Novel Functions of Death-Associated Protein Kinases through Mitogen-Activated Protein Kinase-Related Signals

2018 ◽  
Vol 19 (10) ◽  
pp. 3031 ◽  
Author(s):  
Mohamed Elbadawy ◽  
Tatsuya Usui ◽  
Hideyuki Yamawaki ◽  
Kazuaki Sasaki
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Family Members ◽  
Mitogen Activated Protein Kinase ◽  
Special Focus ◽  
Main Function ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Death Associated Protein Kinase ◽  
Mitogen Activated Protein

Death associated protein kinase (DAPK) is a calcium/calmodulin-regulated serine/threonine kinase; its main function is to regulate cell death. DAPK family proteins consist of DAPK1, DAPK2, DAPK3, DAPK-related apoptosis-inducing protein kinases (DRAK)-1 and DRAK-2. In this review, we discuss the roles and regulatory mechanisms of DAPK family members and their relevance to diseases. Furthermore, a special focus is given to several reports describing cross-talks between DAPKs and mitogen-activated protein kinases (MAPK) family members in various pathologies. We also discuss small molecule inhibitors of DAPKs and their potential as therapeutic targets against human diseases.

scholarly journals 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region.

1996 ◽  
Vol 16 (3) ◽  
pp. 868-876 ◽  
Author(s):  
G Sithanandam ◽  
F Latif ◽  
F M Duh ◽  
R Bernal ◽  
U Smola ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Kinase ◽  
Small Cell Lung Cancer ◽  
Suppressor Gene ◽  
Small Cell ◽  
Mitogen Activated Protein Kinase ◽  
Small Cell Lung ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Mitogen Activated Protein

NotI linking clones, localized to the human chromosome 3p21.3 region and homozygously deleted in small cell lung cancer cell lines NCI-H740 and NCI-H1450, were used to search for a putative tumor suppressor gene(s). One of these clones, NL1G210, detected a 2.5-kb mRNA in all examined human tissues, expression being especially high in the heart and skeletal muscle. Two overlapping cDNA clones containing the entire open reading frame were isolated from a human heart cDNA library and fully characterized. Computer analysis and a search of the GenBank database to reveal high sequence identity of the product of this gene to serine-threonine kinases, especially to mitogen-activated protein kinase-activated protein kinase 2, a recently described substrate of mitogen-activated kinases. Sequence identitiy was 72% at the nucleotide level and 75% at the amino acid level, strongly suggesting that this protein is a serine-threonine kinase. Here we demonstrate that the new gene, referred to as 3pK (for chromosome 3p kinase), in fact encodes a mitogen-activated protein kinase-regulated protein serine-threonine kinase with a novel substrate specificity.

scholarly journals Design principles underpinning the regulatory diversity of protein kinases

2012 ◽  
Vol 367 (1602) ◽  
pp. 2529-2539 ◽  
Author(s):  
Krishnadev Oruganty ◽  
Natarajan Kannan
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Structural Features ◽  
Kinase Domain ◽  
Conformational Flexibility ◽  
Phosphoryl Transfer ◽  
Core Component ◽  
Protein Kinase Domain ◽  
The Core ◽  
Complex Modes

Protein phosphorylation in eukaryotes is carried out by a large and diverse family of protein kinases, which display remarkable diversity and complexity in their modes of regulation. The complex modes of regulation have evolved as a consequence of natural selection operating on protein kinase sequences for billions of years. Here we describe how quantitative comparisons of protein kinase sequences from diverse organisms, in particular prokaryotes, have contributed to our understanding of the structural organization and evolution of allosteric regulation in the protein kinase domain. An emerging view from these studies is that regulatory diversity and complexity in the protein kinase domain evolved in a ‘modular’ fashion through elaboration of an ancient core component, which existed before the emergence of eukaryotes. The core component provided the conformational flexibility required for ATP binding and phosphoryl transfer in prokaryotic kinases, but evolved into a highly regulatable domain in eukaryotes through the addition of exaggerated structural features that facilitated tight allosteric control. Family and group-specific features are built upon the core component in eukaryotes to provide additional layers of control. We propose that ‘modularity’ and ‘conformational flexibility’ are key evolvable traits of the protein kinase domain that contributed to its extensive regulatory diversity and complexity.

scholarly journals Selenoproteins Protect Against Avian Liver Necrosis by Metabolizing Peroxides and Regulating Receptor Interacting Serine Threonine Kinase 1/Receptor Interacting Serine Threonine Kinase 3/Mixed Lineage Kinase Domain-Like and Mitogen-Activated Protein Kinase Signaling

2021 ◽  
Vol 12 ◽  
Author(s):  
Tong Li ◽  
Jing Zhang ◽  
Peng-Jie Wang ◽  
Zi-Wei Zhang ◽  
Jia-Qiang Huang
Keyword(s):  
Protein Kinase ◽  
Basal Diet ◽  
Kinase Domain ◽  
Mitogen Activated Protein Kinase ◽  
Liver Necrosis ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Mitogen Activated Protein ◽  
Se Deficiency ◽  
Protein Kinase Signaling

Liver necroptosis of chicks is induced by selenium (Se)/vitamin E (VE) deficiencies and may be associated with oxidative cell damage. To reveal the underlying mechanisms of liver necrosis, a pool of the corn–soy basal diet (10 μg Se/kg; no VE added), a basal diet plus all-rac-α-tocopheryl acetate (50 mg/kg), Se (sodium selenite at 0.3 mg/kg), or both of these nutrients were provided to day-old broiler chicks (n = 40/group) for 6 weeks. High incidences of liver necrosis (30%) of chicks were induced by –SE–VE, starting at day 16. The Se concentration in liver and glutathione peroxidase (GPX) activity were decreased (P < 0.05) by dietary Se deficiency. Meanwhile, Se deficiency elevated malondialdehyde content and decreased superoxide dismutase (SOD) activity in the liver at weeks 2 and 4. Chicks fed with the two Se-deficient diets showed lower (P < 0.05) hepatic mRNA expression of Gpx1, Gpx3, Gpx4, Selenof, Selenoh, Selenok, Selenom, Selenon, Selenoo, Selenop, Selenot, Selenou, Selenow, and Dio1 than those fed with the two Se-supplemented diets. Dietary Se deficiency had elevated (P < 0.05) the expression of SELENOP, but decreased the downregulation (P < 0.05) of GPX1, GPX4, SELENON, and SELENOW in the liver of chicks at two time points. Meanwhile, dietary Se deficiency upregulated (P < 0.05) the abundance of hepatic proteins of p38 mitogen-activated protein kinase, phospho-p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, phospho-c-Jun N-terminal kinase, extracellular signal-regulated kinase, phospho-mitogen-activated protein kinase, receptor-interacting serine-threonine kinase 1 (RIPK1), receptor-interacting serine-threonine kinase 3 (RIPK3), and mixed lineage kinase domain-like (MLKL) at two time points. In conclusion, our data confirmed the differential regulation of dietary Se deficiency on several key selenoproteins, the RIPK1/RIPK3/MLKL, and mitogen-activated protein kinase signaling pathway in chicks and identified new molecular clues for understanding the etiology of nutritional liver necrosis.

Ability of PknA, a mycobacterial eukaryotic-type serine/threonine kinase, to transphosphorylate MurD, a ligase involved in the process of peptidoglycan biosynthesis

2008 ◽  
Vol 415 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Meghna Thakur ◽  
Pradip K. Chakraborti
Keyword(s):  
Protein Kinases ◽  
Solid Phase ◽  
Morphological Changes ◽  
Binding Assays ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Peptidoglycan Biosynthesis ◽  
Vitro Binding ◽  
Solid Phase Binding

Eukaryotic-type serine/threonine protein kinases in bacteria have been implicated in controlling a host of cellular activities. PknA is one of eleven such protein kinases from Mycobacterium tuberculosis which regulates morphological changes associated with cell division. In the present study we provide the evidence for the ability of PknA to transphosphorylate mMurD (mycobacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate-ligase), the enzyme involved in peptidoglycan biosynthesis. Its co-expression in Escherichia coli along with PknA resulted in phosphorylation of mMurD. Consistent with these observations, results of the solid-phase binding assays revealed a high-affinity in vitro binding between the two proteins. Furthermore, overexpression of m-murD in Mycobacterium smegmatis yielded a phosphorylated protein. The results of the present study therefore point towards the possibility of mMurD being a substrate of PknA.

scholarly journals SEL-5, A Serine/Threonine Kinase That Facilitates lin-12 Activity in Caenorhabditis elegans

Genetics ◽  
1999 ◽  
Vol 153 (4) ◽  
pp. 1641-1654 ◽  
Author(s):  
Hanna Fares ◽  
Iva Greenwald
Keyword(s):  
Cell Fate ◽  
Point Mutations ◽  
Kinase Domain ◽  
Terminal Region ◽  
Serine Threonine Kinase ◽  
Intracellular Domain ◽  
Cell Fate Decisions ◽  
Threonine Kinase ◽  
Amino Terminal ◽  
Fate Decision

Abstract Ligands present on neighboring cells activate receptors of the LIN-12/Notch family by inducing a proteolytic cleavage event that releases the intracellular domain. Mutations that appear to eliminate sel-5 activity are able to suppress constitutive activity of lin-12(d) mutations that are point mutations in the extracellular domain of LIN-12, but cannot suppress lin-12(intra), the untethered intracellular domain. These results suggest that sel-5 acts prior to or during ligand-dependent release of the intracellular domain. In addition, sel-5 suppression of lin-12(d) mutations is tissue specific: loss of sel-5 activity can suppress defects in the anchor cell/ventral uterine precursor cell fate decision and a sex myoblast/coelomocyte decision, but cannot suppress defects in two different ventral hypodermal cell fate decisions in hermaphrodites and males. sel-5 encodes at least two proteins, from alternatively spliced mRNAs, that share an amino-terminal region and differ in the carboxy-terminal region. The amino-terminal region contains the hallmarks of a serine/threonine kinase domain, which is most similar to mammalian GAK1 and yeast Pak1p.

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