Featured
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| Open AccessHypoxia induced responses are reflected in the stromal proteome of breast cancer
The role of hypoxia and metabolic reprogramming in breast cancer remains to be explored. Here, the authors investigate the landscape of secreted proteins in response to hypoxia in breast cancer cell lines and identify a stromal-based hypoxia profile in breast cancer tissue.
- Silje Kjølle
- , Kenneth Finne
- & Lars A. Akslen
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Article
| Open AccessA pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis
Sepsis can cause organ damage through disparate immunological and metabolic processes. Here the authors demonstrate a proteomics-based scoring strategy for quantifying quantitative and organotypic changes in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.
- Tirthankar Mohanty
- , Christofer A. Q. Karlsson
- & Johan Malmström
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Article
| Open AccessSignaling mechanisms in renal compensatory hypertrophy revealed by multi-omics
The authors used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.
- Hiroaki Kikuchi
- , Chung-Lin Chou
- & Mark A. Knepper
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Article
| Open AccessPPP2R1A regulates migration persistence through the NHSL1-containing WAVE Shell Complex
The WAVE regulatory complex activates Arp2/3 at the cell cortex and in membrane protrusions to generate persistent cell migration. Here authors show that PPP2R1A, a scaffold subunit of protein phosphatase 2, associates with an alternative form of the WAVE complex where WAVE, the subunit that activates Arp2/3, is replaced by NHSL1.
- Yanan Wang
- , Giovanni Chiappetta
- & Alexis M. Gautreau
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Article
| Open AccessChemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid
Lipoic acid is a food supplement and approved neuropathy drug but lacks known molecular targets. Here, Lechner et al. employ chemoproteomic target deconvolution to demonstrate that (R)- but not (S)-lipoic acid stereoselectively inhibits histone deacetylases at physiologically achievable doses.
- Severin Lechner
- , Raphael R. Steimbach
- & Bernhard Kuster
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Article
| Open AccessN-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics
Cysteine is a popular target of covalent drugs and can undergo redox modifications. Here, the authors developed cysteine probes, N-acryloylindole-alkynes, for imaging and chemoproteomics to study cysteine oxidation and to identify targetable hotspots by small molecule compounds.
- Tin-Yan Koo
- , Hinyuk Lai
- & Clive Yik-Sham Chung
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Article
| Open AccessRevealing proteome-level functional redundancy in the human gut microbiome using ultra-deep metaproteomics
Here, Li et al. show that functional redundancy, which has not previously been quantified at the proteome level, can arise when different microbes play similar roles in the gut microbiome, revealing that proteomes are nested among gut microbes, favoring high functional redundancy.
- Leyuan Li
- , Tong Wang
- & Daniel Figeys
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Article
| Open AccessTHRONCAT: metabolic labeling of newly synthesized proteins using a bioorthogonal threonine analog
Incorporating bioorthogonally-modified amino acids into newly synthesized proteins allows studying the nascent proteome, but current methods often require special conditions or are toxic to cells. Here, the authors develop a method that uses β-ethynylserine to label nascent proteins under standard conditions without harming cells.
- Bob J. Ignacio
- , Jelmer Dijkstra
- & Kimberly M. Bonger
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Article
| Open AccessMulti-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health
Daly, Danson and colleagues employ a multi-omic approach in neuroglioma cells to characterise endolysosomal dysfunction caused by perturbation of the evolutionarily conserved Retromer complex, highlighting Retromer’s neuroprotective function.
- James L. Daly
- , Chris M. Danson
- & Peter J. Cullen
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Article
| Open AccessDecoding protein methylation function with thermal stability analysis
Methylation is a common modification that affects protein function but, compared to other modifications, our knowledge is limited. Here, the authors use a method based on thermal stability to study how protein methylation regulates processes such as mRNA binding proteins and chromosome compaction.
- Cristina Sayago
- , Jana Sánchez-Wandelmer
- & Javier Munoz
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Article
| Open AccessGenetically encoded photocatalytic protein labeling enables spatially-resolved profiling of intracellular proteome
Mapping the subcellular organization of proteins is crucial for understanding their biological functions. Here, the authors develop a genetically encoded photocatalytic labeling method for profiling the subcellular proteome in multiple organelles.
- Fu Zheng
- , Chenxin Yu
- & Peng Zou
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Article
| Open AccessSmall-sample learning reveals propionylation in determining global protein homeostasis
The development of a new smallsample learning framework, KprFunc, leads to the discovery of an important role for lysine propionylation in determining global protein homeostasis, mediated by a critical propionylation site on histone H2B, H2BK17pr.
- Ke Shui
- , Chenwei Wang
- & Yu Xue
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Article
| Open AccessCell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation
“In-depth cell-selective proteomics and secretomics has remained challenging. Here, the authors devise an optimised azidonorleucine labelling, mass spectrometry method and detect over 10,000 proteins in a pancreatic ductal adenocarcinoma model.
- Jonathan J. Swietlik
- , Stefanie Bärthel
- & Felix Meissner
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Article
| Open AccessLarge-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs
Protein-protein interactions underlie all aspects of a viral infection. Here the authors employ a pan-viral approach for systematic identification of motif-mediated interactions between viral and human proteins and show that the information can be used to find targets for antiviral drug development.
- Filip Mihalič
- , Leandro Simonetti
- & Ylva Ivarsson
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Article
| Open AccessDeepFLR facilitates false localization rate control in phosphoproteomics
Protein phosphorylation is a critical modification in many cellular processes. Here, the authors present DeepFLR, a deep learning-based framework to accurately predict phosphopeptide tandem mass spectra and effectively control false localization rates in phosphoproteomics.
- Yu Zong
- , Yuxin Wang
- & Liang Qiao
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Article
| Open AccessPepQuery2 democratizes public MS proteomics data for rapid peptide searching
Billions of MS/MS spectra are available in public proteomics data repositories, but their usage has been limited to informatics experts. Here, the authors provide a solution to democratize these data for rapid peptide searching and demonstrate utilities in a wide range of biological applications
- Bo Wen
- & Bing Zhang
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Article
| Open AccessNext-generation large-scale binary protein interaction network for Drosophila melanogaster
Maps of protein-protein interactions (PPIs) help identify new components of pathways, complexes, and processes. In this work, state-of-the-art methods are used to identify binary Drosophila PPIs, generating broadly useful physical and data resources.
- Hong-Wen Tang
- , Kerstin Spirohn
- & Stephanie E. Mohr
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Article
| Open AccessThe RNA-binding protein landscapes differ between mammalian organs and cultured cells
Characterization of RNA-binding proteins (RBPs) in tissues has been hampered by technical constraints. Here, the authors describe ex vivo eRIC, a method for global profiling of RBPs active in mammalian organs, and report comprehensive RBP atlases from mouse brain, kidney and liver.
- Joel I. Perez-Perri
- , Dunja Ferring-Appel
- & Matthias W. Hentze
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Article
| Open AccessMultiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19
In this work, authors take a multiomics and microfluidics-based approach to elucidate the mechanism of endothelial damage in critical illness associated with SARS-CoV-2.
- Samuel Druzak
- , Elizabeth Iffrig
- & Cheryl L. Maier
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| Open AccessWorkflow enabling deepscale immunopeptidome, proteome, ubiquitylome, phosphoproteome, and acetylome analyses of sample-limited tissues
Patient samples are often available in limited amounts, restricting the number of possible omics analyses. Here the authors present MONTE, a workflow that enables serial HLA-I and HLA-II immunopeptidome, ubiquitylome, proteome, phosphoproteome, and acetylome data collection from patient samples.
- Jennifer G. Abelin
- , Erik J. Bergstrom
- & Steven A. Carr
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| Open AccessComprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes
Duodenal cancer (DC) has complex subtypes and undergoes complicated morphological changes throughout progression, so understanding the molecular basis is crucial. Here, the authors perform a proteogenomics analysis of 156 DCs, revealing molecular subtypes as well as the roles of smoking, AARS1 and PARP1.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
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Article
| Open AccessPhytochrome B photobodies are comprised of phytochrome B and its primary and secondary interacting proteins
Phytochrome is a photoreceptor forming a membraneless organelle called a photobody. The authors isolated the photobody and found that the photobody is made of not only phytochrome but also its primary and secondary interacting proteins.
- Chanhee Kim
- , Yongmin Kwon
- & Giltsu Choi
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Article
| Open AccessIntegrative proteogenomic characterization of early esophageal cancer
The progression of oesophageal squamous cell carcinoma (ESCC) from early to advanced stages requires comprehensive molecular characterisation. Here, the authors perform a proteogenomics analysis of ESCC patient samples across nine histopathological stages and three phases, identifying key alterations and paths for progression.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
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Article
| Open AccessTandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans
Diagnosis of rare, unpredictable, drug-induced liver injury (DILI) is a significant challenge for patients, clinicians, and drug development. Here, the authors discover, evaluate, and validate potential blood biomarkers to diagnose DILI and distinguish it from alternative causes of liver injury.
- Kodihalli C. Ravindra
- , Vishal S. Vaidya
- & Shashi K. Ramaiah
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Article
| Open AccessStructural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
Tumour suppressors are inhibited in cancers and their reactivation could provide novel therapy opportunities. Here, the authors study the structural mechanism by which human tumour suppressor Protein Phosphatase 2A is inhibited in breast cancer cells by the oncoprotein CIP2A.
- Karolina Pavic
- , Nikhil Gupta
- & Jukka Westermarck
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| Open AccessPhosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance
The failure of metabolic tissues to respond to insulin is an early marker of type 2 diabetes. Here, the authors show, using global phosphoproteomics, that insulin resistance is caused by a marked rewiring of both canonical and non-canonical insulin signalling, and includes dysregulated GSK3 activity.
- Daniel J. Fazakerley
- , Julian van Gerwen
- & Sean J. Humphrey
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Article
| Open AccessRescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub
The 16p11.2 duplication confers risk for autism and schizophrenia, but the disease mechanisms are unknown. Here, the authors use proteomics to show dysregulation of synaptic and epilepsy-associated protein networks in the cortex of model mice, and demonstrate that correcting Prrt2 gene dosage rescues circuit hypersynchrony and behavioural phenotypes.
- Marc P. Forrest
- , Marc Dos Santos
- & Peter Penzes
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Article
| Open AccessGenome-wide genotype-serum proteome mapping provides insights into the cross-ancestry differences in cardiometabolic disease susceptibility
Integrating genetic information with circulating proteomics can help understand mechanisms of disease. Here, the authors conduct genome-wide association analyses of the serum proteome in 2,958 Han Chinese individuals, uncovering proteins which may contribute to ancestry differences in cardiometabolic disease susceptibility.
- Fengzhe Xu
- , Evan Yi-Wen Yu
- & Ju-Sheng Zheng
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Article
| Open AccessSpatial proteomics reveals secretory pathway disturbances caused by neuropathy-associated TECPR2
Disease-associated mutations in the protein TECPR2 have so far been mainly studied with respect to autophagy. Using complementary proteomics approaches, the authors identify trafficking and sorting defects along the secretory pathway upon TECPR2 deficiency and provide evidence that TECPR2 associates with the ER-Golgi interface.
- Karsten Nalbach
- , Martina Schifferer
- & Christian Behrends
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Article
| Open AccessMultilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer
The molecular differences between the two major gastric cancer subtypes diffuse-type gastric cancer (DGC) and intestinaltype gastric cancer (IGC) remain to be investigated. Here, integrated analysis of proteome, phospho-proteome and transcription factor activity for DGC and IGC reveals potential subtypes.
- Wenhao Shi
- , Yushen Wang
- & Chen Ding
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Article
| Open AccessThe ubiquitination landscape of the influenza A virus polymerase
Influenza A virus replication relies on host cell-derived ubiquitination of the viral polymerase. Here, Günl et al. show that site-specific ubiquitination of PB1-K578 is acquired during infection and facilitates spatiotemporal control of polymerase dimerization and NP binding.
- Franziska Günl
- , Tim Krischuns
- & Linda Brunotte
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Article
| Open AccessAccelerating inhibitor discovery for deubiquitinating enzymes
Deubiquitinases (DUBs) are key signaling enzymes, many of which lack selective inhibitors. Chan et al. pair a DUB-focused covalent library to mass spectrometry activity-based protein profiling, leading to selective hits against 23 endogenous DUBs and a first-in-class VCPIP1 probe with nanomolar potency.
- Wai Cheung Chan
- , Xiaoxi Liu
- & Sara J. Buhrlage
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Article
| Open AccessSample multiplexing-based targeted pathway proteomics with real-time analytics reveals the impact of genetic variation on protein expression
Targeted proteomics enables robust hypothesis-driven research. Here, Yu et al. present a multiplexed approach for targeted pathway proteomics and apply it to quantify protein families across 480 fully genotyped Diversity Outbred mice, revealing impacts of genetic variation on protein expression and lipid metabolism.
- Qing Yu
- , Xinyue Liu
- & Steven P. Gygi
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Article
| Open AccessProteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
The proteogenomic landscape of diffuse gliomas remains to be explored. Here, the authors perform proteogenomic characterisation of diffuse gliomas, investigate the functional role of genomic alterations and suggest three proteomic subgroups.
- Yunzhi Wang
- , Rongkui Luo
- & Chen Ding
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Article
| Open AccessThe SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators
Here the authors establish the SPOC domain as a universal reader of the RNA Pol II CTD code and a versatile reader of phosphoserine marks found in co- and post-transcriptional regulators such as m6A writer and reader proteins.
- Lisa-Marie Appel
- , Vedran Franke
- & Dea Slade
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| Open AccessBenchmarking commonly used software suites and analysis workflows for DIA proteomics and phosphoproteomics
Many software suites and spectral libraries have been developed for DIA proteomics data analysis. Here, the authors create benchmark data sets to evaluate four commonly used software tools combined with seven spectral libraries in both global proteomics and phosphoproteomics analysis.
- Ronghui Lou
- , Ye Cao
- & Wenqing Shui
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Article
| Open AccessBenchmarking tools for detecting longitudinal differential expression in proteomics data allows establishing a robust reproducibility optimization regression approach
Longitudinal proteomics holds great promise for biomarker discovery, but the data interpretation has remained a challenge. Here, the authors evaluate several tools to detect longitudinal differential expression in proteomics data and introduce RolDE, a robust reproducibility optimization approach.
- Tommi Välikangas
- , Tomi Suomi
- & Laura L. Elo
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Article
| Open AccessIn-depth mapping of protein localizations in whole tissue by micro-scaffold assisted spatial proteomics (MASP)
Accurate protein mapping on whole-tissue levels provides critical insights into diseases/therapies. Here, the authors described a novel spatial proteomics method, based on tissue compartmentalization using a 3D-printed micro-scaffold, generated thousands of protein maps across a whole-tissue slice.
- Min Ma
- , Shihan Huo
- & Jun Qu
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| Open AccesspGlycoQuant with a deep residual network for quantitative glycoproteomics at intact glycopeptide level
Software tools for larger-scale intact glycopeptide quantification lag far behind, which hinders exploring the differential sitespecific glycosylation. Here, the authors report pGlycoQuant, a generic tool with a deep learning model for quantitative glycoproteomics at intact glycopeptide level.
- Siyuan Kong
- , Pengyun Gong
- & Weiqian Cao
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Article
| Open AccessProteogenomic characterization of MiT family translocation renal cell carcinoma
The molecular landscape of microphthalmia transcription factor family translocation renal cell carcinoma tumours remain to be characterised. Here, the authors perform proteogenomic analysis and reveal dysregulation of DNA repair, mTOR signalling and metabolic processes.
- Yuanyuan Qu
- , Xiaohui Wu
- & Chen Ding
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Article
| Open AccessProtein-Peptide Turnover Profiling reveals the order of PTM addition and removal during protein maturation
Metabolic labeling is often used to measure protein turnover. Here the authors show that for interconvertible protein species like phosphoforms metabolic labeling does not provide information on turnover differences, but that the relative order of modification can determine the observed dynamics.
- Henrik M. Hammarén
- , Eva-Maria Geissen
- & Mikhail M. Savitski
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Article
| Open AccessSpatially resolved proteomics via tissue expansion
Spatially resolved proteomics is an emerging approach for mapping proteome heterogeneity. Here, the authors report a method based on the combination of hydrogel-based tissue transformation with mass spectrometry-based proteomics, that enables proteome profiling with a lateral resolution of 160 µm.
- Lu Li
- , Cuiji Sun
- & Kiryl D. Piatkevich
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Article
| Open AccessDNA methylation-based classification of sinonasal tumors
Sinonasal tumour diagnosis can be complicated by the heterogeneity of disease and classification systems. Here, the authors use machine learning to classify sinonasal undifferentiated carcinomas into 4 molecular classe with differences in differentiation state and clinical outcome.
- Philipp Jurmeister
- , Stefanie Glöß
- & David Capper
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Article
| Open AccessInsights into protein post-translational modification landscapes of individual human cells by trapped ion mobility time-of-flight mass spectrometry
Single-cell proteomics is an emerging approach to study cellular heterogeneity but its coverage is still limited. Here, the authors develop a single-cell proteomics approach with improved protein sequence coverage, allowing them to quantify PTMs and characterize effects of inhibitor treatment in single human cells.
- Benjamin C. Orsburn
- , Yuting Yuan
- & Namandjé N. Bumpus
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Article
| Open AccessEnhanced access to the human phosphoproteome with genetically encoded phosphothreonine
Protein phosphorylation is a ubiquitous post-translational modification used to regulate cellular processes and proteome architecture by modulating protein-protein interactions. Here the authors optimize genetically encoded phosphothreonine to study the regulation of CHK2 kinase using large-scale DNA arrays that enable phosphoproteome expression techniques to identify sitespecific overlap between CHK2 substrates and 14-3-3 interactions.
- Jack M. Moen
- , Kyle Mohler
- & Jesse Rinehart
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Article
| Open AccessAlphaPeptDeep: a modular deep learning framework to predict peptide properties for proteomics
Deep learning (DL) has been frequently used in mass spectrometry-based proteomics but there is still a lot of potential. Here, the authors develop a framework that enables building DL models to predict arbitrary peptide properties with only a few lines of code.
- Wen-Feng Zeng
- , Xie-Xuan Zhou
- & Matthias Mann
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Article
| Open AccessMetabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population
Four T2D subtypes were previously identified: severe insulin deficient, severe insulin resistant, mild obesity-related, and mild age-related diabetes. Here, the authors show that these subtypes can be translated to an Arabic population and identify distinct subtype-specific metabolic and proteomic signatures.
- Shaza B. Zaghlool
- , Anna Halama
- & Karsten Suhre
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Article
| Open AccessAn extracellular receptor tyrosine kinase motif orchestrating intracellular STAT activation
Specificity in signaling activated by receptor tyrosine kinases is typically attributed to characteristics of their intracellular domains. Here, the authors demonstrate that an extracellular receptor sequence motif controls intracellular signaling as a result of extracellular glycan interactions.
- Katri Vaparanta
- , Anne Jokilammi
- & Klaus Elenius
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Article
| Open AccessConnecting multiple microenvironment proteomes uncovers the biology in head and neck cancer
The biological understanding of poor prognosis associated with lymph node metastasis in head and neck cancer (HNC) remains crucial. Here, a proteomic characterisation of 140 multisite samples from a 59-HNC patient cohort and machine learning reveals potential biomarkers and metastasis related signatures.
- Ariane F. Busso-Lopes
- , Leandro X. Neves
- & Adriana F. Paes Leme