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Proteome profiling of phosphatidylinositol-5-phosphate 4-kinase type 2A and 2B knockdown cells identify modifications in key regulators involved in cell homeostasis and genome integrity

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Abstract

Phosphatidylinositol-5-phosphate 4-kinases (PIP4K) are multiple cellular process regulatory lipid kinases. PIP4K2A and PIP4K2B are overexpressed in cancer. The recently reported kinase-independent role of PIP4K2A and PIP4K2B underscore the complexity of the underlying molecular changes and mechanisms involved. Here, we show proteome analysis of PIP4K2A, PIP4K2B and PIP4K2A/2B co-depleted osteosarcoma cells to reflect changes in protein expression and their post-translational modifications. PIP4K2A depletion mainly affects ribosome assembly, translation and cell proliferation. Proteins of the apoptotic process, DNA repair, and cell division are mainly affected in PIP4K2B knockdown cells. PIP4K2A/2B co-depletion affects proteins regulating vesicle transport, cell motility, RNA splicing, and cell division. PIP4K depletion also affects post-translational modifications (phosphorylation, acetylation) of proteins involved mainly in nucleosome organization, mRNA splicing, and DNA replication. In addition, we observed PIP4K2A and PIP4K2B overexpression in cells harbouring K-Ras G12V or G12D mutations. Collectively, our results show that single or co-depletion of the PIP4K isoforms regulate proteins participating in metabolism and maintenance of genome integrity. Given that PIP4K2A and PIP4K2B alter proteins related to genome instability and their role in cancer, these enzymes could be promising therapeutic targets for cells experiencing genotoxic stress conditions.

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Data availability

The processed data are shared on JPOST. https://repository.jpostdb.org/preview/913033704619b8641c16a8. Access key: 8637. (Announced ID; JPST001387, PXD029802). jPOSTrepo is an international standard data repository for proteomes.

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Acknowledgements

We thank CSIR-IITR confocal microscopy, proteomics, cell culture and RT-PCR facility for their support. Murine embryonic fibroblast (MEF) K-Ras 4B G12V were from Dr Rachel K. Bagni (Frederick National Laboratory for Cancer Research (FNLCR) NCI, USA). CMT-93 were gifted by Dr Florian Greten (Germany) and K-Ras G12D plasmid was from Addgene. We thank Dr Abhilasha Kanaujia for editorial assistance. P.A. and V.K.Y. were supported by CSIR-SRF fellowships. Work in A.K. lab is supported by Wellcome Trust/DBT India Alliance intermediate fellowship (Grant number: IA/16/2/502721) and CSIR intramural funding. A.K. is DBT-Wellcome India Alliance Intermediate fellow. CSIR manuscript number IITR/SEC/2021-2022/57.

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Authors and Affiliations

  1. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India

    Poorwa Awasthi, Ankur Kumar Srivastava, Vipin Kumar Yadav, Radhika Singh & Amit Kumar

  2. CSIR-Indian Institute of Toxicology Research, Lucknow, Uttar Pradesh, 226001, India

    Poorwa Awasthi, Ankur Kumar Srivastava, Vipin Kumar Yadav, Smriti Singh Yadav & Amit Kumar

  3. Institute of Systems Genetics, New York University, New York, NY, USA

    Gururaj Rao Kidiyoor

  4. CSIR- Institute of Microbial Technology, Chandigarh, India

    Radhika Singh & Amit Kumar

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  1. Poorwa Awasthi
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PA: planned all experiments, performed all the experiments, analysed the data presented in all figures, assisted in manuscript writing and prepared figures. AKS: data analysis using proteome discoverer, figure presentation, Run HRMS equipment. SSY: data analysis using proteome discoverer. VKY: assisted in HRMS experiment. RS: assisted in autophagy experiment. GRK: data analysis. AK: conceptualized study, provided resource, designed, planned experiments, wrote the manuscript.

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Correspondence to Amit Kumar.

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Awasthi, P., Srivastava, A.K., Yadav, V.K. et al. Proteome profiling of phosphatidylinositol-5-phosphate 4-kinase type 2A and 2B knockdown cells identify modifications in key regulators involved in cell homeostasis and genome integrity. GENOME INSTAB. DIS. 3, 88–107 (2022). https://doi.org/10.1007/s42764-022-00060-7

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