Dataset Information

Phosphoproteomic profiling discriminates between myeloid and lymphoid pathotypes in early RA synovium

ABSTRACT: Background: Rheumatoid arthritis (RA) is a complex heterogenous autoimmune disease and achieving long term disease remission is an elusive goal for patients, thus implying improvement in drug targeting is necessary. Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in RA. Therefore, oral inhibitors of specific kinases, such as Cyclin Dependent Kinases (CDKs) and Janus Kinase (JAKs), are under development or have been approved. However, the cell signalling mechanisms in treatment naïve RA patients is yet to be explored, which may facilitate targeted therapy stratification. Methods: We undertook phosphoproteome and total proteome analysis of 8 pre-treatment synovial biopsies of RA patients using label-free mass spectrometry. Results: The analysis revealed a clear separation of the phosphoproteome and proteome profile between the lymphoid and myeloid RA pathotypes. Differential expression analysis and function enrichment showed that the degree of inflammatory state and specific signalling activities are associated with different RA pathotypes. The lymphoid pathotype was enriched with immunological pathways and associated with Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted kinases not previously linked to RA, such as Serine/Threonine Protein Kinase N1 (PKN1) in the lymphoid pathotype and Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotypes. Certain phosphosites were also highly correlated with clinical features, such as Disabled Homolog 2 (DAB2)-Ser723 with Disease Activity Score (DAS)-28, and so these may be potential biomarkers of disease progression and response. Conclusions: These data provide evidence that specific phosphoproteome and proteome signatures are associated with different RA pathotypes and may have clinical utility for stratifying patients as part of a personalised medicine approach.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Layer Of Synovial Tissue, Synovial Tissue

DISEASE(S): Rheumatoid Arthritis

SUBMITTER: Vinothini Rajeeve

LAB HEAD: Professor Pedro R Cutillas

PROVIDER: PXD044963 | Pride | 2024-08-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	QE2_Cos_Exp3_PP_11.raw	Raw
	QE2_Cos_Exp3_PP_11.raw.-1.mgf	Mgf
	QE2_Cos_Exp3_PP_13.raw	Raw
	QE2_Cos_Exp3_PP_13.raw.-1.mgf	Mgf
	QE2_Cos_Exp3_PP_15.raw	Raw

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Publications

Phosphoproteomic profiling of early rheumatoid arthritis synovium reveals active signalling pathways and differentiates inflammatory pathotypes.

Çubuk Cankut C Lau Rachel R Cutillas Pedro P Rajeeve Vinothini V John Christopher R CR Surace Anna E A AEA Hands Rebecca R Fossati-Jimack Liliane L Lewis Myles J MJ Pitzalis Costantino C

Arthritis research & therapy 20240612 1

<h4>Background</h4>Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to meas ...[more]

PMID: 38867295

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