Dataset Information

Phosphorylation sites on Sec16 mediated by CK1alpha

ABSTRACT: Phosphorylation sites on Sec16 identified by phosphoproteomic analysis following CK1alpha-dependent phosphorylation in the presence of Sec13.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Masaki Wakabayashi

PROVIDER: PXD066860 | JPOST Repository | Fri Sep 12 00:00:00 BST 2025

REPOSITORIES: jPOST

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Dataset's files

Source:

			Action	DRS
	210806_01Sec16GelExt_Ct_1659.d.zip	Other
	210806_02Sec16GelExt_phosphoA_1661.d.zip	Other
	210806_03Sec16GelExt_phosphoB_1663.d.zip	Other
	220324_DrSaito_phosphosite.zip	Other

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Project description:Dysregulated kinase activity drives oncogenic signalling, perturbs cellular homeostasis, and promotes tumour progression. Despite major success in targeting kinases therapeutically, the downstream consequences of kinase inhibition and the mechanisms underlying drug resistance remain incompletely understood. One of the most frequent oncogenic kinase mutations, BRAFV600E, constitutively activates the MAPK pathway and represents a major therapeutic target in melanoma and other cancers. However, the functional relevance of most phosphorylation events downstream of BRAF signalling is unknown, limiting mechanistic interpretation and rational therapeutic design. Here, we established a global, multi-omic model of BRAF inhibition response in BRAFV600E-mutant melanoma cells by integrating time-resolved phosphoproteomics, biophysical PTM-proteomics, transcriptomics, and thermal proteome profiling. Our ultradeep phosphoproteomic analysis revealed widespread phosphorylation changes upon Dabrafenib treatment, while biophysical phosphoproteomics uncovered phosphorylation events associated with altered solubility and subcellular localisation, indicative of biomolecular condensation and nuclear reorganisation. Integration of these modalities into a network-based mechanistic model enabled the prioritisation of functionally relevant phosphorylation sites and kinases. Experimental validation confirmed CDK9, CLK3, and TNIK as key regulators of BRAFV600E signalling and as candidate targets for combinatorial inhibition strategies capable of re-sensitising resistant melanoma cells in a synthetic lethal manner. The transcription factor ETV3 emerged from the network as a previously unrecognised effector of oncogenic BRAF signalling. Using phosphosite-specific biophysical data, imaging, and FRAP experiments, we demonstrated that ETV3 phosphorylation controls its DNA-binding kinetics. Functional assays combining ETV3 knockdown, metabolomics, and drug screening revealed that ETV3 modulates transcriptional and metabolic responses to BRAF inhibition, linking oncogenic signalling to metabolic rewiring. Together, this study provides a comprehensive systems-level framework that connects phosphorylation dynamics to protein function and cellular phenotype, highlights ETV3 as a novel signalling node, and illustrates how multi-omic, site-resolved network models can reveal actionable mechanisms of kinase-driven oncogenesis.

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Phosphorylation sites on Sec16 mediated by CK1alpha

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