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The mitochondrial transporter SFXN1 is critical for Complex III integrity and cellular metabolism

ABSTRACT: Mutations in acylglycerol kinase (AGK) leads to Sengers syndrome, a rare disease characterized by skeletal myopathy, hypertrophic cardiomyopathy, and cataracts. AGK, in vitro, produces lysophosphatidic acid and phosphatidic acid via phosphorylation of monoacylglycerol and diacylglycerol, accordingly. AGK is also a component of the TIM22 import machinery in the inner mitochondrial membrane and, independent of its kinase activity, has been shown to mediate the import of mitochondrial carrier family (SLC25) members. We compared the proteomes of mitochondria from HEK293 WT and AGK KO cells in order to identify additional candidate substrates of the TIM22 translocase that relies on AGK.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney Epithelium

SUBMITTER: Akhilesh Pandey

LAB HEAD: Steven Claypool

PROVIDER: PXD019826 | Pride | 2020-06-18

REPOSITORIES: Pride

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Activating Mutations in PIK3CA result in Widespread Modulation of the Tyrosine Phosphoproteome

Project description:The human oncogene PIK3CA is frequently mutated in human cancers. The two hotspot mutations in PIK3CA, E545K and H1047R, have been shown to regulate widespread signaling events downstream of AKT. However, the impact of these activating mutations on the tyrosine phosphorylation signaling in the cell has not been studied. Here, we performed a global phosphotyrosine profiling using isogenic knockin cell lines containing these activating mutations. We identified 824 unique phosphopeptides from 308 proteins. We found a surprisingly widespread modulation of tyrosine phosphorylation levels of proteins in the knockin mutant cells, with many of the regulated proteins involved in important biological processes, including those in the cytoskeletal migration pathways and kinase regulated signaling. We observed a widespread modulation of the tyrosine kinome, with 24 of the tyrosine kinases showing either upregulation or downregulation in phosphorylation levels. Many of the regulated phosphosites that we identified were located in the kinase domain or the canonical activating sites, indicating that the kinases were active and hence their downstream signaling pathways. Our study thus shows that the activating mutations in PIK3CA result in widespread tyrosine signaling regulation, in addition to the serine/threonine signaling pathways activated by the canonical PI3K-AKT axis.

2018-10-24 | PXD001460 | Pride

Spatiotemporal proteomics uncovers cathepsin-dependent host cell death during bacterial infection

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