Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Kinobead profiling of PITCOINs1-3

ABSTRACT: Phosphatidylinositol 3-kinase type 2a (PI3KC2a) and related class II PI 3-kinase isoforms are of rising biomedical interest because of their crucial roles in endocytic membrane dynamics, cell division and signalling, angiogenesis, and platelet morphology and function. Herein we report the development and characterization of PITCOINs, potent and highly selective small molecule inhibitors of PI3KC2 catalytic activity. PITCOIN compounds exhibit strong selectivity towards PI3KC2 due to their unique mode of interaction with the ATP binding site of the enzyme. We demonstrate that acute inhibition of PI3KC2-mediated synthesis of phosphatidylinositol 3-phosphates by PITCOINs impairs endocytic membrane dynamics and membrane remodelling during platelet-dependent thrombus formation. To our knowledge PITCOINs are the first potent and selective cell permeable inhibitors of PI3KC2a function with potential biomedical applications ranging from thrombosis to diabetes and cancer.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: Polina Prokofeva

LAB HEAD: Bernhard Kuster

PROVIDER: PXD032284 | Pride | 2022-08-24

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	5089_BA10_057042_S00_A00_R1.raw	Raw
	5089_BA11_057043_S00_A00_R1.raw	Raw
	5089_BA12_057044_S00_A00_R1.raw	Raw
	5089_BA1_057033_S00_A00_R1.raw	Raw
	5089_BA2_057034_S00_A00_R1.raw	Raw

Items per page:

1 - 5 of 42

Similar Datasets

Dasatinib for the treatment of gastric cancer

Project description:Gastric cancer (GC) represents a major health problem, remaining the fifth most common type of cancer and the third leading cause of cancer-related death worldwide with only few targeted therapies available to date. The positive effect of kinase inhibitors on many different types of cancers has prompted the investigation of these compounds also in GC. In a screen of FDA-approved kinase inhibitors, dasatinib was found as a potent inhibitor of gastric cancer cells migration and invasion. In order to identify the kinases involved proteomics analysis was performed identifying SRC kinases, Ephrins and DDR1 as potential molecular targets.

2020-05-26 | PXD012953 | Pride

Transcriptome comparison of monocytes, activated CD4 T cells, and activated CD8 T cells in healthy human peripheral blood

Project description:Molecular tether-mediated extracellular targeted protein degradation (ePTD) emerges as a promising drug modality. The existing strategies for ePTD have exploited several membrane degrader proteins. However, the current panel of ePTD degraders clearly needs to be expanded, as a given degrader may present tissue-dependent expression and activity. Based on screening of >50 receptors on endocytic rates and on their tissue distribution, we established a resource of potential endocytic carriers that may mediate effective ePTD. We subsequently introduced an adaptable design to assemble “Selected endocytic carrier-targeting chimera (SecTAC)” based on bispecific antibody constructs. The resultant modular chimeras, by co-opting newly identified degraders, directed efficient internalization of extracellular protein cargoes (or nucleic acids). Importantly, shaped by the availability of the corresponding endocytic carrier, the output of a SecTAC could present cell subset selectivity. We also validated the therapeutic potential of SecTAC agents for targeting several cell membrane proteins in tumor cells and primary T cells. Furthermore, we adapted the platform to establish multi-cargo tethers that triggered simultaneous degradation of two cell surface proteins in primary T cells. Taken together, our SecTAC platform has laid the foundation for development of preclinical drug candidates capable of inducing extracellular and membrane target degradation in desirable population of cells.

2024-04-13 | GSE263462 | GEO

Platelets favor the outgrowth of established metastases

Project description:Despite abundant evidence demonstrating that platelets foster metastasis, anti- platelet agents have low therapeutic potential due to the risk of hemorrhages. In addition, whether platelets can regulate metastasis at the late stages of the disease remains unknown. In this study, we subjected syngeneic models of metastasis to various thrombocytopenic regimes to show that platelets provide a biphasic contribution to metastasis. While potent intravascular binding of platelets to tumor cells efficiently promotes metastasis, platelets further support the outgrowth of established metastases via immune suppression. Genetic depletion and pharmacological targeting of the platelet-specific receptor GPVI in humanized mouse models efficiently reduced the growth of established metastases, independently of active platelet binding to tumor cells in the bloodstream. Our study is the first to demonstrate therapeutic efficacy when targeting animals bearing growing metastases. It further identifies GPVI as the first molecular target whose inhibition can impair metastasis without inducing collateral hemostatic perturbations.

2024-03-10 | E-MTAB-13864 | biostudies-arrayexpress

Spns1 controls megalin dependent endocytosis via iron misregulation

Project description:Proximal tubule endocytosis is essential for protecting the kidney from potentially damaging proteinuria and for mediating metabolic pathways, such as the activation of Vitamin D. We have identified the lysosomal membrane protein, Spns1, as a novel iron conductance that is indispensable for the normal endocytic function of the proximal tubule. Conditional knockout of Spns1 with a Cre-lox system in megalin-expressing cells in mice leads to arrest of both pinocytosis and receptor-mediated endocytosis in the proximal tubule. This endocytic defect is associated with iron overload in proximal tubules as measured by immunofluorescence of ferritin abundance and by a reduction in nascent TfRc mRNA transcripts. We have recapitulated previous findings in drosophila and zebrafish that Spns1 knockout causes endolysosomal dysfunction including abnormally enlarged lysosomes. The endocytic defect resulting from conditional Spns1 knockout can be rescued nutritionally with an iron deficient diet or genetically through double knockout of both Spns1 and the Fe2+ transporter, DMT1. Surprisingly, the endocytic defect in mice with Spns1 conditional knockout occurs despite normal megalin expression at the proximal tubule apical membrane. This data raises the possibilty that post-translational regulation of megalin activation may be nutrient-responsive.

2024-09-06 | GSE268837 | GEO

Quantification and discovery of sequence determinants of protein per mRNA amount in 29 human tissues

Project description:We analyzed the contribution of known sequence determinants of protein synthesis and degradation and novel mRNA and protein sequence motifs that we found by association testing. In order to investigate the functional understanding of novel mRNA motifs, an RNA competitive-binding assay was developed to systematically identify motif-specific RNA binding proteins and to measure interaction strength thereof.

2019-02-20 | PXD010153 | Pride

Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation

Project description:Glycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. LC-MS was used to characterize the isolates from cells stimulated with PDGF-BB-conjugated nanoparticles (endocytic vesicle fraction) or PDGF-BB plus unconjugated nanoparticles (control). Taken together, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics.

2023-06-19 | MSV000092208 | MassIVE

RNA-seq of brown adipocyte mouse cells treated with different concentrations of DNA origami structures with organized insulin molecules or free insulin molecules against untreated controls

Project description:Insulin binds the insulin receptor (IR), which in turn has showed to form nanoclusters at the cell membrane. Trying to exploit the nanoscale spatial organization of IR, we developed rod-like insulin-DNA-origami nanostructures carrying different numbers of insulin molecules. These structures (referred to as NanoRods, or NR) were then utilized to investigate receptor activity to spatial distribution of insulin molecules. One part of this investigation was to study the transcriptional response of brown adipocytes treated with NR bound to one insulin (NR-1) and NR bound to seven insulin (NR-7), and compare to untreated controls. Furthermore, free insulin was also used to ensure that similar pathways were activated when using NR-bound insulin.

2023-07-03 | E-MTAB-12160 | biostudies-arrayexpress

FAM92A1 Regulates Neural Structure and Function through Membrane Remodeling

Project description:The Bin/amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in the regulation of mitochondrial ultrastructure and ciliogenesis. However, the physiological role of FAM92A1 in the brain, particularly in neurons with specialized membrane architecture, remains unexplored. Here, we demonstrate that FAM92A1 is prominently expressed in the brain and neurons during early mouse embryonic development. FAM92A1 knockout mice display brain morphology alterations, age-associated memory decline, and cognitive deficits. Moreover, the absence of FAM92A1 triggers hippocampal neuron degeneration and disrupts neuronal complexity and synaptic plasticity. Crucially, FAM92A1 deficiency leads to anomalies in membrane remodeling and disturbances in neuronal endocytic processes. Through analysis of the crystal structure of the FAM92A1 BAR domain, we unveil its intrinsic capability to form dimers, contributing to a distinctive curved conformation critical for membrane remodeling. By combining structural and molecular simulation, we further gain a comprehensive understanding of how FAM92A1 interacts with membranes to induce lipid clustering and generate membrane curvature. In summary, our study provides valuable insights into the physiological function of FAM92A1 in the brain. It uncovers the molecular mechanisms through which FAM92A1 regulates synaptic plasticity and neural function by influencing membrane remodeling and endocytic processes.

2024-07-05 | GSE264202 | GEO

14-3-3ζ controls adipocyte progenitor cell cycle and differentiation via Gli3-dependent p27Kip expression

Project description:14-3-3 proteins facilitate cytoplasmic-nuclear shuttling of transcription factors.Adipocyte differentiation requires the function of critical transcription factors to drive the development of a mature adipocyte. The aim of the study was to investigate if 14-3-3ζ is required for the adipogenic transcriptional program. Examination of the transcriptome in siCon- and si14-3-3ζ-transfected 3T3-L1 cells undergoing differentiation at t=0, 24, and 48 hours.

2015-07-23 | E-GEOD-60745 | biostudies-arrayexpress

A selective autophagy pathway for endocytic protein condensates

Project description:Autophagy eliminates cytoplasmic content selected by autophagy receptors, which link cargoes to the membrane bound autophagosomal ubiquitin-like protein Atg8/LC3. Here, we discover a selective autophagy pathway for protein condensates formed by endocytic proteins. In this pathway, the endocytic yeast protein Ede1 functions as a selective autophagy receptor. Distinct domains within Ede1 bind Atg8 and mediate phase separation into condensates. Both properties are necessary for an Ede1-dependent autophagy pathway for endocytic proteins, which differs from regular endocytosis, does not involve other known selective autophagy receptors, but requires the core autophagy machinery. Cryo-electron tomography of Ede1-containing condensates – at the plasma membrane and in autophagic bodies – shows a phase-separated compartment at the beginning and end of the Ede1-mediated selective autophagy pathway. Our results imply an important role of autophagy in surveillance of membraneless compartments

2020-11-23 | PXD019083 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data