scholarly journals LTK is an ER-resident receptor tyrosine kinase that regulates secretion

2019 ◽  
Author(s):  
Federica G. Centonze ◽  
Veronika Reiterer ◽  
Karsten Nalbach ◽  
Kota Saito ◽  
Krzysztof Pawlowski ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Secretory Proteins ◽  
Golgi Transport ◽  
Er Exit Sites ◽  
Local Signaling ◽  
Er Export ◽  
Pharmacologic Inhibition

AbstractThe endoplasmic reticulum (ER) is a key regulator of cellular proteostasis because it controls folding, sorting and degradation of secretory proteins. Much has been learned about how environmentally triggered signaling pathways regulate ER function, but only little is known about local signaling at the ER. The identification of ER-resident signaling molecules will help gain a deeper understanding of the regulation of ER function and thus of proteostasis. Here, we show that leukocyte tyrosine kinase (LTK) is an ER-resident receptor tyrosine kinase. Depletion of LTK as well as its pharmacologic inhibition reduces the number of ER exit sites and slows ER-to-Golgi transport. Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module the potential to regulate proteostasis.

scholarly journals LTK is an ER-resident receptor tyrosine kinase that regulates secretion

2019 ◽  
Vol 218 (8) ◽  
pp. 2470-2480 ◽  
Author(s):  
Federica G. Centonze ◽  
Veronika Reiterer ◽  
Karsten Nalbach ◽  
Kota Saito ◽  
Krzysztof Pawlowski ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Secretory Proteins ◽  
Golgi Transport ◽  
Er Exit Sites ◽  
Local Signaling ◽  
Er Export ◽  
Pharmacologic Inhibition

The endoplasmic reticulum (ER) is a key regulator of cellular proteostasis because it controls folding, sorting, and degradation of secretory proteins. Much has been learned about how environmentally triggered signaling pathways regulate ER function, but only little is known about local signaling at the ER. The identification of ER-resident signaling molecules will help gain a deeper understanding of the regulation of ER function and thus of proteostasis. Here, we show that leukocyte tyrosine kinase (LTK) is an ER-resident receptor tyrosine kinase. Depletion of LTK as well as its pharmacologic inhibition reduces the number of ER exit sites and slows ER-to-Golgi transport. Furthermore, we show that LTK interacts with and phosphorylates Sec12. Expression of a phosphoablating mutant of Sec12 reduces the efficiency of ER export. Thus, LTK-to-Sec12 signaling represents the first example of an ER-resident signaling module with the potential to regulate proteostasis.

scholarly journals Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 513 ◽  
Author(s):  
Marina Leite ◽  
Miguel S. Marques ◽  
Joana Melo ◽  
Marta T. Pinto ◽  
Bruno Cavadas ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Receptor Activation ◽  
Degradation Pathway ◽  
Mrna Levels ◽  
H Pylori

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.

scholarly journals Registered report: Widespread potential for growth factor-driven resistance to anticancer kinase inhibitors

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Edward Greenfield ◽  
Erin Griner ◽  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Cancer Biology ◽  
Kinase Inhibitors ◽  
Open Science ◽  
Downstream Signaling ◽  
Rtk Inhibitors ◽  
Block Sensitivity

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered Report describes the proposed replication plan of key experiments from ‘Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors’ by Wilson and colleagues, published in Nature in 2012 (<xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The experiments that will be replicated are those reported in Figure 2B and C. In these experiments, Wilson and colleagues show that sensitivity to receptor tyrosine kinase (RTK) inhibitors can be bypassed by various ligands through reactivation of downstream signaling pathways (Figure 2A; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>), and that blocking the receptors for these bypassing ligands abrogates their ability to block sensitivity to the original RTK inhibitor (Figure 2C; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

scholarly journals A Folate- and Vitamin B12-Deficient Diet Decreases the Latency and Increases the Incidence of Mammary Tumors in MMTV-ErbB2 Transgenic Mice

2021 ◽  
Author(s):  
Zhengzheng Xiao ◽  
Guoliang Yao ◽  
Yongxuan Liu ◽  
Chunling Zhao
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Vitamin B12 ◽  
Signaling Pathways ◽  
Mammary Tumor ◽  
Receptor Tyrosine Kinase ◽  
Tumor Development ◽  
Deficient Diet ◽  
Tyrosine Kinase 2 ◽  
Folate And Vitamin B12

Abstract There has been controversy regarding folate- and vitamin B12-deficient diet (FVD)-induced hyperhomocysteinemia (HHcy) associated with breast cancer risk in most published epidemiological studies. Thus, the present study designed experiments to assess the causal association between FVD-induced HHcy and mammary tumor risk, as well as to identify the relative underlying mechanism. In this study, mammary tumor development was examined in mouse mammary tumor virus (MMTV)-erb-b2 receptor tyrosine kinase 2 (ErbB2) mice fed with a control AIN-93G diet or a FVD diet. MMTV-ErbB2 mice fed with the FVD diet displayed elevated blood levels of the amino acid homocysteine, a shorter tumor latency and an increased tumor multiplicity compared with the controls. The expression levels of key markers in the receptor tyrosine kinase and estrogen receptor (ER) signaling pathways, including phosphorylated (p)-Akt, p-Erk, p-ERα and Cyclin D1, were elevated in mammary tissues from MMTV-ErbB2 mice fed the FVD diet compared with mice fed with control diet. These data suggested that FVD-induced HHcy may promote mammary tumor development and decrease tumor latency, possibly by activating the epidermal growth factor receptor/ErbB2 and ERα signaling pathways. Therefore, examining the signaling mechanisms and identifying the relative metabolic pathways underlying mammary tumor promotion following FVD-induced HHcy may provide a novel strategy for breast cancer prevention and treatment.

scholarly journals Vesicular and uncoated Rab1-dependent cargo carriers facilitate ER to Golgi transport

2020 ◽  
Vol 133 (14) ◽  
pp. jcs239814 ◽  
Author(s):  
Laura M. Westrate ◽  
Melissa J. Hoyer ◽  
Michael J. Nash ◽  
Gia K. Voeltz
Keyword(s):  
Endoplasmic Reticulum ◽  
De Novo ◽  
Coated Vesicle ◽  
First Person ◽  
Coat Proteins ◽  
Animal Cells ◽  
Golgi Transport ◽  
Er Exit Sites ◽  
Copii Vesicles ◽  
Export System

ABSTRACTSecretory cargo is recognized, concentrated and trafficked from endoplasmic reticulum (ER) exit sites (ERES) to the Golgi. Cargo export from the ER begins when a series of highly conserved COPII coat proteins accumulate at the ER and regulate the formation of cargo-loaded COPII vesicles. In animal cells, capturing live de novo cargo trafficking past this point is challenging; it has been difficult to discriminate whether cargo is trafficked to the Golgi in a COPII-coated vesicle. Here, we describe a recently developed live-cell cargo export system that can be synchronously released from ERES to illustrate de novo trafficking in animal cells. We found that components of the COPII coat remain associated with the ERES while cargo is extruded into COPII-uncoated, non-ER associated, Rab1 (herein referring to Rab1a or Rab1b)-dependent carriers. Our data suggest that, in animal cells, COPII coat components remain stably associated with the ER at exit sites to generate a specialized compartment, but once cargo is sorted and organized, Rab1 labels these export carriers and facilitates efficient forward trafficking.This article has an associated First Person interview with the first author of the paper.

scholarly journals Steady-state Regulation of Secretory Cargo Export by Inositol Trisphosphate Receptors and Penta EF Hand Proteins

2020 ◽  
Author(s):  
Aaron Held ◽  
Jennet Hojanazarova ◽  
John Sargeant ◽  
Corina Madreiter-Sokolowski ◽  
Roland Mali ◽  
...  
Keyword(s):  
Steady State ◽  
Inositol Trisphosphate ◽  
State Regulation ◽  
Outer Coat ◽  
Inositol Trisphosphate Receptors ◽  
Golgi Transport ◽  
Ef Hand ◽  
Er Exit Sites ◽  
Er Export ◽  
Partial Depletion

ABSTRACTER Ca2+ regulates ER-to-Golgi transport machinery. Sustained Ca2+ signaling by inositol trisphosphate receptors (IP3Rs) leads to depression of cargo export through activation of penta EF hand protein (PEF) ALG-2 which reduces outer COPII coat at ER exit sites (ERES). However, we do not know whether tonic Ca2+ signals during steady-state conditions affect ER export rates and if so by what mechanisms. Here we report that partial depletion of IP3 receptors from NRK epithelial cells causes a marked increase of basal ER export of the transmembrane glycoprotein cargo VSV-G. The increased ER-to-Golgi transport required ALG-2 and was actuated by decreased peflin and increased ALG-2 at ER exit sites (ERES) – a condition previously demonstrated to stimulate COPII-dependent ER export. Upon IP3R depletion the amount of outer coat at ERES increased, the opposite to what occurs during ALG-2-dependent inhibition of secretion during agonist-driven Ca2+ signaling. The increased ER export correlated with reduced spontaneous cytosolic Ca2+ oscillations caused by the reduced number of Ca2+ release channels. IP3R depletion also unexpectedly resulted in partial depletion of ER luminal Ca2+ stores. The low Ca2+ conditions appeared to decrease both ALG-2 and peflin expression levels somewhat, but these were the only detectable expression changes in COPII trafficking machinery and the Ca2+ decrease had no detectable impact on ER stress. We conclude that at steady state, IP3Rs produce tonic Ca2+ signals that suppress the basal rate of ER export by maintaining lower outer coat targeting to ERES.

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