scholarly journals Targeted Inhibition of mTOR Signaling Improves Sensitivity of Esophageal Squamous Cell Carcinoma Cells to Cisplatin

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Guiqin Hou ◽  
Shuai Yang ◽  
Yuanyuan Zhou ◽  
Cong Wang ◽  
Wen Zhao ◽  
...  
Keyword(s):  
Cell Number ◽  
Carcinoma Cells ◽  
Serine Threonine Kinase ◽  
Western Blots ◽  
Threonine Kinase ◽  
Evolutionarily Conserved ◽  
Targeted Inhibition ◽  
Proliferation In Vitro

mTOR is an evolutionarily conserved serine-threonine kinase with a central role in cell growth, invasion, and metastasis of tumors, and is activated in many cancers. The aims of this study were to investigate the expression of mTOR in ESCC tissues and its relationship with progression of ESCC and measure the changes of sensitivity of ESCC cells to cisplatin after cells were treated with mTOR siRNA by WST-8 assays, TUNEL, RT-PCR, and western blots in vitro and in vivo. The results showed that the expression of mTOR was higher in ESCC specimens than that in normal esophageal tissues and its expression was closely correlated with the TNM stage of ESCC. mTOR siRNA significantly increased the sensitivity of the EC9706 cells to cisplatin at proliferation in vitro and in vivo. The growth of ESCC xenografts was significantly inhibited by mTOR siRNA or cisplatin, and the cell number of apoptosis was obviously increased after xenografts were treated with mTOR siRNA or cisplatin alone, especially when mTOR siRNA combined with cisplatin. The present study demonstrates that the expression of mTOR has important clinical significance and inhibition of mTOR pathway by mTOR siRNA can improve the sensitivity of ESCC cells to cisplatin.

scholarly journals WNK4 Kinase: from structure to physiology

2021 ◽  
Author(s):  
Adrian Rafael Murillo-de-Ozores ◽  
Alejandro Rodriguez-Gama ◽  
Hector Carbajal-Contreras ◽  
Gerardo Gamba ◽  
Maria Castaneda-Bueno
Keyword(s):  
Oxidative Stress ◽  
Mouse Models ◽  
Serine Threonine Kinase ◽  
Gene Encoding ◽  
Threonine Kinase ◽  
Physiological Conditions ◽  
Different Levels ◽  
Familial Hyperkalemic Hypertension

With No Lysine (K) kinase 4 (WNK4) belongs to a serine-threonine kinase family characterized by the atypical positioning of its catalytic lysine. Despite the fact that WNK4 has been found in many tissues, the majority of its study has revolved around its function in the kidney, specifically as a positive regulator of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron. This is explained by the description of gain-of-function mutations in the gene encoding WNK4 that cause Familial Hyperkalemic Hypertension (FHHt). This disease is mainly driven by increased downstream activation of the Ste20-related Proline Alanine Rich Kinase (SPAK)/Oxidative Stress Responsive Kinase 1 (OSR1)-NCC pathway, which increases salt reabsorption in the DCT and indirectly impairs renal K+ secretion. Here, we review the large volume of information that has accumulated about different aspects of WNK4 function. We first review the knowledge on WNK4 structure and enumerate the functional domains and motifs that have been characterized. Then, we discuss WNK4 physiological functions based on the information obtained from in vitro studies and from a diverse set of genetically modified mouse models with altered WNK4 function. We then review in vitro and in vivo evidence on the different levels of regulation of WNK4. Finally, we go through the evidence that has suggested how different physiological conditions act through WNK4 to modulate NCC activity.

scholarly journals Protein Serine/Threonine Kinase StkP Positively Controls Virulence and Competence in Streptococcus pneumoniae

2004 ◽  
Vol 72 (4) ◽  
pp. 2434-2437 ◽  
Author(s):  
Jose Echenique ◽  
Aras Kadioglu ◽  
Susana Romao ◽  
Peter W. Andrew ◽  
Marie-Claude Trombe
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lung Infection ◽  
Signaling Network ◽  
Serine Threonine Kinase ◽  
Positive Regulation ◽  
Threonine Kinase

ABSTRACT In the Streptococcus pneumoniae genome, stkP, encoding a membrane-associated serine/threonine kinase, is not redundant (L. Novakova, S. Romao, J. Echenique, P. Branny, and M.-C. Trombe, unpublished results). The data presented here demonstrate that StkP belongs to the signaling network involved in competence triggering in vitro and lung infection and bloodstream invasion in vivo. In competence, functional StkP is required for activation of comCDE upstream of the autoregulated ring orchestrated by the competence-stimulating peptide. This is the first description of positive regulation of comCDE transcription in balance with its repression by CiaRH.

scholarly journals Regulation of Yeast Actin Cytoskeleton-Regulatory Complex Pan1p/Sla1p/End3p by Serine/Threonine Kinase Prk1p

2001 ◽  
Vol 12 (12) ◽  
pp. 3759-3772 ◽  
Author(s):  
Guisheng Zeng ◽  
Xianwen Yu ◽  
Mingjie Cai
Keyword(s):  
Actin Cytoskeleton ◽  
Regulatory Protein ◽  
Strong Support ◽  
Stable Complex ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization

The serine/threonine kinase Prk1p is known to be involved in the regulation of the actin cytoskeleton organization in budding yeast. One possible function of Prk1p is the negative regulation of Pan1p, an actin patch regulatory protein that forms a complex in vivo with at least two other proteins, Sla1p and End3p. In this report, we identified Sla1p as another substrate for Prk1p. The phosphorylation of Sla1p by Prk1p was established in vitro with the use of immunoprecipitated Prk1p and in vivo with the use ofPRK1 overexpression, and was further supported by the finding that immunoprecipitated Sla1p contained PRK1- and ARK1-dependent kinase activities. Stable complex formation between Prk1p and Sla1p/Pan1p in vivo could be observed once the phosphorylation reaction was blocked by mutation in the catalytic site of Prk1p. Elevation of Prk1p activities in wild-type cells resulted in a number of deficiencies, including those in colocalization of Pan1p and Sla1p, endocytosis, and cell wall morphogenesis, likely attributable to a disintegration of the Pan1p/Sla1p/End3p complex. These results lend a strong support to the model that the phosphorylation of the Pan1p/Sla1p/End3p complex by Prk1p is one of the important mechanisms by which the organization and functions of the actin cytoskeleton are regulated.

scholarly journals Hydroxysteroid Sulfotransferase SULT2B1b Promotes Hepatocellular Carcinoma Cells Proliferation In Vitro and In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e60853 ◽  
Author(s):  
Xiaoming Yang ◽  
Yali Xu ◽  
Fenghua Guo ◽  
Yanxia Ning ◽  
Xiuling Zhi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Carcinoma Cells ◽  
Hepatocellular Carcinoma Cells ◽  
Proliferation In Vitro

scholarly journals Inhibition of Bcr serine kinase by tyrosine phosphorylation.

1996 ◽  
Vol 16 (3) ◽  
pp. 998-1005 ◽  
Author(s):  
J Liu ◽  
Y Wu ◽  
G Z Ma ◽  
D Lu ◽  
L Haataja ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Phosphorylation ◽  
Kinase Activity ◽  
Philadelphia Chromosome ◽  
Wild Type ◽  
Serine Kinase ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

The first exon of the BCR gene encodes a new serine/threonine protein kinase. Abnormal fusion of the BCR and ABL genes, resulting from the formation of the Philadelphia chromosome (Ph), is the hallmark of Ph-positive leukemia. We have previously demonstrated that the Bcr protein is tyrosine phosphorylated within first-exon sequences by the Bcr-Abl oncoprotein. Here we report that in addition to tyrose 177 (Y-177), Y-360 and Y283 are phosphorylated in Bcr-Abl proteins in vitro. Moreover, Bcr tyrosine 360 is phosphorylated in vivo within both Bcr-Abl and Bcr. Bcr mutant Y177F had a greatly reduced ability to transphosphorylate casein and histone H1, whereas Bcr mutants Y177F and Y283F had wild-type activities. In contrast, the Y360F mutation had little effect on Bcr's autophosphorylation activity. Tyrosine-phosphorylated Bcr, phosphorylated in vitro by Bcr-Abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of Bcr. Similarly, the isolation of Bcr from cells expressing Bcr-Abl under conditions that preserve phosphotyrosine residues also reduced Bcr's kinase activity. These results indicate that tyrosine 360 of Bcr is critical for the transphosphorylation activity of Bcr and that in Ph-positive leukemia, Bcr serine/threonine kinase activity is seriously impaired.

scholarly journals A PERK-Like Receptor Kinase Interacts with the Geminivirus Nuclear Shuttle Protein and Potentiates Viral Infection

2006 ◽  
Vol 80 (13) ◽  
pp. 6648-6656 ◽  
Author(s):  
Lilian H. Florentino ◽  
Anésia A. Santos ◽  
Mariana R. Fontenelle ◽  
Guilherme L. Pinheiro ◽  
Francisco M. Zerbini ◽  
...  
Keyword(s):  
Intracellular Transport ◽  
Kinase Domain ◽  
Receptor Protein ◽  
Nuclear Shuttle Protein ◽  
Serine Threonine Kinase ◽  
Viral Dna ◽  
Functional Link ◽  
Threonine Kinase

ABSTRACT The nuclear shuttle protein (NSP) from bipartite geminiviruses facilitates the intracellular transport of viral DNA from the nucleus to the cytoplasm and acts in concert with the movement protein (MP) to promote the cell-to-cell spread of the viral DNA. A proline-rich extensin-like receptor protein kinase (PERK) was found to interact specifically with NSP of Cabbage leaf curl virus (CaLCuV) and of tomato-infecting geminiviruses through a yeast two-hybrid screening. The PERK-like protein, which we designated NsAK (for NSP-associated kinase), is structurally organized into a proline-rich N-terminal domain, followed by a transmembrane segment and a C-terminal serine/threonine kinase domain. The viral protein interacted stably with defective versions of the NsAK kinase domain, but not with the potentially active enzyme, in an in vitro binding assay. In vitro-translated NsAK enhanced the phosphorylation level of NSP, indicating that NSP functions as a substrate for NsAK. These results demonstrate that NsAK is an authentic serine/threonine kinase and suggest a functional link for NSP-NsAK complex formation. This interpretation was corroborated by in vivo infectivity assays showing that loss of NsAK function reduces the efficiency of CaLCuV infection and attenuates symptom development. Our data implicate NsAK as a positive contributor to geminivirus infection and suggest it may regulate NSP function.

Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4531-4539 ◽  
Author(s):  
Malgorzata Nieborowska-Skorska ◽  
Grazyna Hoser ◽  
Plamen Kossev ◽  
Mariusz A. Wasik ◽  
Tomasz Skorski
Keyword(s):  
Cell Cycle Progression ◽  
Critical Role ◽  
Cell Protection ◽  
Serine Threonine Kinase ◽  
Antiapoptotic Protein ◽  
Threonine Kinase ◽  
Sh2 Domains ◽  
Enhanced Expression

BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an important role in leukemogenesis. The downstream effectors of the BCR/ABL→STAT5 pathway remain poorly defined. We show here that expression of the antiapoptotic protein A1, a member of the Bcl-2 family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL. This up-regulation requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played a key role in the BCR/ABL-mediated cell protection from apoptosis. In addition, pim-1 promoted proliferation of the BCR/ABL-transformed cells. Both A1 and pim-1 were required to induce interleukin 3–independent cell growth, inhibit activation of caspase 3, and stimulate cell cycle progression. Moreover, simultaneous up-regulation of both A1 and pim-1 was essential for in vitro transformation and in vivo leukemogenesis mediated by BCR/ABL. These data indicate that induction of A1 and pim-1 expression may play a critical role in the BCR/ABL-dependent transformation.

scholarly journals STK33/ERK2 signal pathway contribute the tumorigenesis of colorectal cancer HCT15 cells

2019 ◽  
Vol 19 ◽  
Author(s):  
Shengjun Zhang ◽  
Minli Liu ◽  
Haoyu Wu ◽  
Kaiyu Wang
Keyword(s):  
Colorectal Cancer ◽  
Ex Vivo ◽  
Kinase Assay ◽  
In Vivo Studies ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Upstream Kinase ◽  
Colorectal Cancer Patients

: Serine/threonine kinase 33 (STK33) is a serine/threonine kinase, and participates in many apoptotic process. Herein, we found that the extracellular signal-regulated kinase 2 (ERK2) was a substrate of STK33. STK33 phosphorylated ERK2and increased the activity of ERK2 and promote the tumorigenesis of colorectal cancer HCT15 cells. Clinical simple showed that STK33 was highly expression in colorectal cells and tissues. Ex vivo and in vivo studies demonstrated that STK33 accelerate tumorigenic properties in JB6C141 cells and athymic nude rats. In vitro kinase assay results indicated that STK33 can phosphorylate ERK2. Ex vivo studies further showed that STK33 can bind with ERK2 and take part in the regulation of ERKs signaling pathway. In short, our results showed that STK33 is a novel upstream kinase of ERK2. It may provide a better prospect for STK33 based prevention and treatment for colorectal cancer patients.

scholarly journals An Inducible and Secreted Eukaryote-Like Serine/Threonine Kinase of Salmonella enterica Serovar Typhi Promotes Intracellular Survival and Pathogenesis

2014 ◽  
Vol 83 (2) ◽  
pp. 522-533 ◽  
Author(s):  
Nagaraja Theeya ◽  
Atri Ta ◽  
Sayan Das ◽  
Rahul S. Mandal ◽  
Oishee Chakrabarti ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Functional Characterization ◽  
Systemic Infection ◽  
Serine Threonine Kinase ◽  
Content Type ◽  
Threonine Kinase ◽  
Universal Substrate

Eukaryote-like serine/threonine kinases (eSTKs) constitute an important family of bacterial virulence factors. Genome analysis had predicted putative eSTKs inSalmonella entericaserovar Typhi, although their functional characterization and the elucidation of their role in pathogenesis are still awaited. We show here that the primary sequence and secondary structure of thet4519locus ofSalmonellaTyphi Ty2 have all the signatures of eukaryotic superfamily kinases.t4519encodes a ∼39-kDa protein (T4519), which shows serine/threonine kinase activitiesin vitro. Recombinant T4519 (rT4519) is autophosphorylated and phosphorylates the universal substrate myelin basic protein. Infection of macrophages results in decreased viability of the mutant (Ty2Δt4519) strain, which is reversed by gene complementation. Moreover, reactive oxygen species produced by the macrophages signal to the bacteria to induce T4519, which is translocated to the host cell cytoplasm. That T4519 may target a host substrate(s) is further supported by the activation of host cellular signaling pathways and the induction of cytokines/chemokines. Finally, the role of T4519 in the pathogenesis ofSalmonellaTyphi is underscored by the significantly decreased mortality of mice infected with the Ty2Δt4519strain and the fact that the competitive index of this strain for causing systemic infection is 0.25% that of the wild-type strain. This study characterizes the first eSTK ofSalmonellaTyphi and demonstrates its role in promoting phagosomal survival of the bacteria within macrophages, which is a key determinant of pathogenesis. This, to the best of our knowledge, is the first study to describe the essential role of eSTKs in thein vivopathogenesis ofSalmonellaspp.

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