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Background <p>PHIP (PH Interacting Protein) is an Insulin Receptor Substrate 1 (IRS1) interactor protein that binds to acetylated IRS1 through its bromodomain. Due to its involvement in insulin signaling pathway, it is implicated in various malignancies and metabolic disorders. Despite this role, the phosphoregulatory network governing PHIP activity is understudied. Therefore, current study aimed to elucidate the landscape of PHIP phosphorylation and its functional significance in insulin signaling by employing a global phosphoproteomic data integration and harmonization strategy.</p> Results <p>A total of 1008 human phosphoproteomics datasets were used to gather 412 differential regulation datasets exhibiting differential abundance of PHIP phosphopeptides. Seven predominant phosphorylation sites of PHIP (S879, S880, S881, S1281, S1283, S1315, and S1783) were most frequently detected in phosphoproteomics data derived from cell lines and tissue samples. Further, conserved, statistically robust inter-protein co-differential regulation analysis as compared to differential phosphorylation of PHIP showed several upstream kinases (CHEK2, CLK1 and ATM) and interactors (SMARCA4 and NCOA5), which are known to be involved in the insulin signaling pathway. IRS1 and IRS2, which definitively modulate insulin signaling, also showed significant co-differential regulation with PHIP phosphorylation. When cross-validated with CPTAC and cProSite data, PHIP, SMARCA4 and CHEK2 showed differential protein abundance and phosphorylation status in Hepatocellular Carcinoma samples, further linking insulin signaling and liver cancers in connection to PHIP phosphorylation.</p> Conclusions <p>This phosphorylation-centric study suggests the role of phosphorylated PHIP in insulin signaling pathway through modulation and co-differential phosphorylation of key proteins, paving the way for a robust and replicable approach in elucidating putative targets.</p>

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Differential phosphorylation of PHIP phosphopeptides with implications in insulin signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Ayadathil Sujina,
  • Amal Fahma,
  • Suhail Subair,
  • Athira Perunelly Gopalakrishnan,
  • Samseera Ummar,
  • Prathik Basthikoppa Shivamurthy,
  • Rajesh Raju,
  • Poornima Ramesh

摘要

Background

PHIP (PH Interacting Protein) is an Insulin Receptor Substrate 1 (IRS1) interactor protein that binds to acetylated IRS1 through its bromodomain. Due to its involvement in insulin signaling pathway, it is implicated in various malignancies and metabolic disorders. Despite this role, the phosphoregulatory network governing PHIP activity is understudied. Therefore, current study aimed to elucidate the landscape of PHIP phosphorylation and its functional significance in insulin signaling by employing a global phosphoproteomic data integration and harmonization strategy.

Results

A total of 1008 human phosphoproteomics datasets were used to gather 412 differential regulation datasets exhibiting differential abundance of PHIP phosphopeptides. Seven predominant phosphorylation sites of PHIP (S879, S880, S881, S1281, S1283, S1315, and S1783) were most frequently detected in phosphoproteomics data derived from cell lines and tissue samples. Further, conserved, statistically robust inter-protein co-differential regulation analysis as compared to differential phosphorylation of PHIP showed several upstream kinases (CHEK2, CLK1 and ATM) and interactors (SMARCA4 and NCOA5), which are known to be involved in the insulin signaling pathway. IRS1 and IRS2, which definitively modulate insulin signaling, also showed significant co-differential regulation with PHIP phosphorylation. When cross-validated with CPTAC and cProSite data, PHIP, SMARCA4 and CHEK2 showed differential protein abundance and phosphorylation status in Hepatocellular Carcinoma samples, further linking insulin signaling and liver cancers in connection to PHIP phosphorylation.

Conclusions

This phosphorylation-centric study suggests the role of phosphorylated PHIP in insulin signaling pathway through modulation and co-differential phosphorylation of key proteins, paving the way for a robust and replicable approach in elucidating putative targets.