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EGFR N-Glycosylation Profile from Colorectal Cancer Cells

ABSTRACT: LC-MS/MS glycoproteomic analysis of EGFR N-glycosylation profile. EGFR immunoprecipitated from colorectal cancer cell lines SW48 (wild-type and ST6Gal1 overexpression) and Caco-2 (wild-type and ST6Gal1 knock-out)

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Henrique Duarte

LAB HEAD: Celso A. Reis

PROVIDER: PXD017914 | Pride | 2021-04-14

REPOSITORIES: Pride

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			Action	DRS
	L20192000195a.msf	Msf
	L20192000195a.pdResult	Other
	L20192000195a.raw	Raw
	L20192000196a.msf	Msf
	L20192000196a.pdResult	Other

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Publications

Terminal α2,6-sialylation of epidermal growth factor receptor modulates antibody therapy response of colorectal cancer cells.

Rodrigues Joana G JG Duarte Henrique O HO Gomes Catarina C Balmaña Meritxell M Martins Álvaro M ÁM Hensbergen Paul J PJ de Ru Arnoud H AH Lima Jorge J Albergaria André A van Veelen Peter A PA Wuhrer Manfred M Gomes Joana J Reis Celso A CA

Cellular oncology (Dordrecht, Netherlands) 20210413 4

<h4>Background</h4>The epidermal growth factor receptor (EGFR) is a key protein involved in cancer development. Monoclonal antibodies targeting EGFR are approved for the treatment of metastatic colorectal cancer (CRC). Despite the beneficial clinical effects observed in subgroups of patients, the acquisition of resistance to treatment remains a major concern. Protein N-glycosylation of cellular receptors is known to regulate physiological processes leading to activation of downstream signaling p ...[more]

PMID: 33847896

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ErbB2 Site-Specific α2,6-Sialylation Regulates Gastric Cancer Cell Sensitivity to Trastuzumab

Project description:The clinical performance of trastuzumab in the treatment of ErbB2-positive gastric cancer is severely hampered by the emergence of molecular resistance. The glycosylation landscape of ErbB2’s extracellular domain, and the molecular mechanisms through which it tunes gastric cell malignancy, including the acquisition of trastuzumab resistance, remain elusive. We show that the expression of ErbB2 sialylated glycoforms holds clinical utility in the prediction of clinical outcome and stratification of gastric cancer patients. In-depth glycoproteomic and glycomic analysis of ErbB2 extracellular region disclosed a site-specific profile in gastric cancer cells. We further demonstrate that ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites within the trastuzumab binding domain. Moreover, the abrogation of ST6Gal1-mediated α2,6-sialylation reshapes ErbB2 glycome and sensitizes gastric cancer cells to trastuzumab-induced cytotoxicity through receptor membrane stabilization and a downregulation of ErbB2 activation. Overall, this data demonstrates that aberrant sialylation tunes the molecular resistance of ErbB2-driven gastric cancer cells to trastuzumab.

2021-05-11 | PXD017609 | Pride

PTX3 structure determination using a hybrid cryo-electron microscopy and AlphaFold approach offers insights into ligand binding and complement activation

Project description:Pattern recognition molecules (PRMs) form an important part of innate immunity and respond to infection and damage via triggering processes such as inflammation. The pentraxin family of soluble PRMs comprises long and short pentraxins, with the former containing unique N-terminal regions unrelated to other proteins or each other. No high-resolution structural information exists about long pentraxins, unlike the short pentraxins where there is an abundance of both X-ray and cryo-electron microscopy (cryoEM) derived structures. This study presents for the first time a high-resolution structure of the prototypical long pentraxin, PTX3. CryoEM yielded a 2.5 Å map of the C-terminal pentraxin domains that revealed a radically different quaternary structure compared to other pentraxins, comprising a glycosylated D4 symmetrical octameric complex stabilised by an extensive disulfide network. The cryoEM map indicated α-helices that extended N-terminal of the pentraxin domains that were not fully resolved. AlphaFold was used to predict the remaining N-terminal structure of the octameric PTX3 complex, revealing two long tetrameric coiled coils with two hinge regions, which was validated using classification of cryoEM 2D averages. The resulting hybrid cryoEM/AlphaFold structure allowed mapping of ligand binding sites, such as C1q and FGF2, as well as rationalisation of previous biochemical data. Given the relevance of PTX3 in conditions ranging from COVID-19 prognosis, cancer progression and female infertility, this structure could be used to inform the understanding and rational design of therapies for these disorders and processes.

2022-10-14 | PXD034602 | Pride

Proinsulin degradation and presentation of a proinsulin B-chain autoantigen involves ER-associated protein degradation (ERAD)-enzyme UBE2G2

Project description:Type 1 diabetes (T1D) is characterized by HLA class I-mediated presentation of autoantigens on the surface of pancreatic β-cells. Recognition of these autoantigens by CD8¬¬+ T cells results in the destruction of pancreatic β-cells and, consequently, insulin deficiency. Most epitopes presented at the surface of β-cells derive from the insulin precursor molecule proinsulin. The intracellular processing pathway(s) involved in the generation of these peptides are poorly defined. In this study, we show that a proinsulin B-chain antigen (PPIB5-14) originates from proinsulin molecules that are processed by ER-associated protein degradation (ERAD) and thus originate from ER-resident proteins. Furthermore, screening genes encoding for E2 ubiquitin conjugating enzymes, we identified UBE2G2 to be involved in proinsulin degradation. These results indicate that insulin-derived peptides, presented by HLA-class I molecules at the cell surface, originate from ER-resident proinsulin that has been dislocated to the cytosol for subsequent degradation. These insights into the pathway involved in the generation of insulin-derived peptides emphasize the importance of proinsulin processing in the ER to T1D pathogenesis and identify novel targets for future therapies that may cure or even prevent T1D.

2024-03-20 | PXD049996 | Pride

Human VAPome Analysis Reveals MOSPD1 and MOSPD3 as Membrane Contact Site Proteins Interacting with FFAT-Related FFNT Motifs

Project description:Membrane contact sites (MCS) are intracellular regions where two organelles come closer to exchange information and material. The majority of the endoplasmic reticulum (ER) MCS are attributed to the ER-localized tether proteins VAPA, VAPB, and MOSPD2. These recruit other proteins to the ER by interacting with their FFAT motifs. Here, we describe MOSPD1 and MOSPD3 as ER-localized tethers interacting with FFAT motif-containing proteins. Using BioID, we identify proteins interacting with VAP and MOSPD proteins and find that MOSPD1 and MOSPD3 prefer unconventional FFAT-related FFNT (two phenylalanines [FF] in a neutral tract) motifs. Moreover, VAPA/VAPB/MOSPD2 and MOSPD1/MOSPD3 assemble into two separate ER-resident complexes to interact with FFAT and FFNT motifs, respectively. Because of their ability to interact with FFNT motifs, MOSPD1 and MOSPD3 could form MCS between the ER and other organelles. Collectively, these findings expand the VAP family of proteins and highlight two separate complexes in control of interactions between intracellular compartments.

2023-06-29 | PXD043399 | Pride

Expression Data From HCMV-Infected Human Monocytes: Role of EGFR

Project description:Human cytomegalovirus (HCMV) induces pro-inflammatory monocytes following infection and we have evidence that EGFR is a key mediator in this early activation. To begin to address how this signalling pathway is responsible for the rapid activation of infected monocytes, we examined the role this pathway played in the transcriptome of infected monocytes. Global transcriptional profiling using cDNA microarrays revealed a significant number of genes, including inflammatory genes, were regulated in a EGFR-dependent manner, identifying this pathway as a key cellular control point in the conversion of monocytes to an activated pro-inflammatory state following HCMV infection. Keywords: Disease state To begin to globally define how EGFR is involved in the HCMV-induced changes in monocyte function, we performed a transcriptome analysis in the presence of inhibitors to the EGFR signalling pathway. Specifically, a cDNA microarray containing 12,625 unique probe sets was utilized to assess the modulation of the monocyte transcriptome at 24 hours post infection in the presence of blocking anti-EGFR antibody and pharmacological agent AG1478 (AG; an EGFR inhibitor). A total of 4 replicates from mock-infected, HCMV-infected, anti-EGFR antibody-pretreated infected and AG-pretreated infected monocytes were analyzed in this study.

2009-09-03 | E-GEOD-17948 | biostudies-arrayexpress

Data Set2: Extensive Rewiring of the EGFR Network in Colorectal Cancer Cells Expressing Transforming Levels of KRASG13D