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<p>MTSS2, a protein predominantly expressed in the brain, plays pivotal roles in cytoskeletal remodeling, synaptic plasticity and neurodevelopmental processes, yet the phosphoregulation process is not much explored. Here, we present a panoramic phosphoproteomic atlas of MTSS2, integrating global human datasets to map predominant phosphosites (S456, S579, S601, S612) enriched in intrinsically disordered regions, which likely serve as regulatory hubs for actin-membrane interactions. Co-phosphoregulation network analysis reveals high-confidence associations with cytoskeletal effectors (e.g., PLEC, MYH9, FHOD1) and Rho/Cdc42 regulators (CDC42EP3/4), forming a coordinated scaffold for filopodia dynamics and membrane curvature. Computational predictions identify MARK2, PAK1/2, and PRKCD as upstream kinases targeting these sites, embedding MTSS2 in polarity, migration, and apoptosis pathways. Clinically, S612 hyperphosphorylation correlates with glioma and breast cancer progression, suggesting oncogenic repurposing, while altered phosphorylation may contribute to MTSS2-related neurodevelopmental disorder (NDD). This phospholandscape illuminates MTSS2 as a tunable integrator of neuronal architecture and tumor suppression, nominating phospho-specific interventions for cytoskeletal disorders.</p> Graphical abstract <p></p>

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Decoding MTSS2 phosphoregulation: its role in cytoskeletal dynamics and clinical implications

  • 期刊论文

  • 发表日期：

    2026年4月15日

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  • Jishna Vijayan,
  • Suhail Subair,
  • Althaf Mahin,
  • Athira Perunelly Gopalakrishnan,
  • Alimath Sambreena,
  • Athira C. Rajeev,
  • Rajesh Raju

摘要

MTSS2, a protein predominantly expressed in the brain, plays pivotal roles in cytoskeletal remodeling, synaptic plasticity and neurodevelopmental processes, yet the phosphoregulation process is not much explored. Here, we present a panoramic phosphoproteomic atlas of MTSS2, integrating global human datasets to map predominant phosphosites (S456, S579, S601, S612) enriched in intrinsically disordered regions, which likely serve as regulatory hubs for actin-membrane interactions. Co-phosphoregulation network analysis reveals high-confidence associations with cytoskeletal effectors (e.g., PLEC, MYH9, FHOD1) and Rho/Cdc42 regulators (CDC42EP3/4), forming a coordinated scaffold for filopodia dynamics and membrane curvature. Computational predictions identify MARK2, PAK1/2, and PRKCD as upstream kinases targeting these sites, embedding MTSS2 in polarity, migration, and apoptosis pathways. Clinically, S612 hyperphosphorylation correlates with glioma and breast cancer progression, suggesting oncogenic repurposing, while altered phosphorylation may contribute to MTSS2-related neurodevelopmental disorder (NDD). This phospholandscape illuminates MTSS2 as a tunable integrator of neuronal architecture and tumor suppression, nominating phospho-specific interventions for cytoskeletal disorders.

Graphical abstract