MassIVE MSV000094459

Partial Public PXD051172

Phosphoproteomics reveals selective induction of signal transduction pathways by different lysophosphatidic acid species in macrophages

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Description

Lysophosphatidic acid (LPA) species, prevalent in the tumor microenvironment (TME), adversely impact various cancers. In ovarian cancer, the 18:0 and 20:4 LPA species in particular are associated with shorter relapse-free survival, indicating distinct effects on cellular signaling networks. Macrophages represent a cell type of high relevance in the TME, but the impact of LPA on them remains obscure. Here, we uncovered distinct LPA-species-specific responses in human monocyte-derived macrophages through unbiased phosphoproteomics, with 87 and 161 phosphosites upregulated by 20:4 and 18:0 LPA, respectively, and only 24 shared sites. Specificity was even more pronounced for downregulated phosphosites (163 versus 5 sites). Considering the frequently high levels of 20:4 LPA in the TME and its association with poor survival, these findings are of relevance for further understanding of cancer promotion and maintenance. Pathway analysis pinpointed RHO/RAC1 GTPase signaling as the predominantly impacted pathway, including AHRGEF and DOCK guanine exchange factors, ARHGAP GTPase activating proteins, and regulatory protein kinases. Consistent with these findings, exposure to 20:4 resulted in strong alterations to the actin filament network and a consequent enhancement of macrophage migration. Moreover, 20:4 LPA induced p38 phosphorylation, a response not mirrored by 20:4 LPA, whereas the pattern for AKT was reversed. Furthermore, RNA profiling identified genes involved in cholesterol/lipid metabolism as selective targets of 20:4 LPA. These findings imply that the two LPA species cooperatively regulate different pathways to support functions essential for pro-tumorigenic macrophages within the TME. These include cellular survival via AKT activation and migration through RHO/RAC1 and p38 signaling. [doi:10.25345/C53J39C17] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Exploris ; Phosphorylation ; Orbitrap ; macrophages ; lysophosphatidic acid

Contact

Principal Investigators:
(in alphabetical order) 		Prof. Dr. Rolf Mueller, Philipps-Universitaet Marburg, Zentrum fuer Tumorbiologie (Tumorbiologie) Institut fuer Molekularbiologie und Tumorforschung (IMT), Germany
Submitting User: Wszymanski

Publications

Raimund Dietze, Witold Szymanski , Kaire Ojasalu, Florian Finkernagel, Andrea Nist, Thorsten Stiewe, Johannes Graumann and Rolf Mueller.
Phosphoproteomics Reveals Selective Regulation of Signaling Pathways by Lysophosphatidic Acid Species in Macrophages.
Cells 2024, 13(10), 810; https://doi.org/10.3390/cells13100810.

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