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<p>The SHROOM protein family (SHROOM1-4) serves as master regulators of actomyosin contractility, apical-basal polarity, and tissue morphogenesis through conserved domains and extensive intrinsically disordered regions (IDRs) that harbour dynamic phosphorylation sites. This study explores their conserved evolutionary patterns, IDRs and integrates ~ 3,800 high-quality human phosphoproteomic datasets to decode co-phospho-regulatory networks of SHROOM1-4, identifying phosphosites per isoform, with few of the SHROOM1 and 3 predominant sites in domain and others clustered near ASD1/ASD2 boundaries. Co-occurrence heatmaps reveal tightly coupled multisite phosphorylation in SHROOM1/3 versus modular, inhibitory patterns in SHROOM2, while SHROOM4 exhibits minimal modification. Upstream kinases, 19 for SHROOM1, 9 for SHROOM2, 7 for SHROOM3 span MAPK, PI3K/AKT, and Rho pathways, with co-phosphorylated kinases, phosphatases, and binary interactors forming dense hubs integrating cytoskeletal, cell cycle, and transcriptional signaling. Dysregulation links SHROOM3 hypophosphorylation to neural tube defects and chronic kidney disease, SHROOM2 to cancer migration/EMT, and SHROOM4 mutations to intellectual disability. By mapping phospho-logic to functional outcomes, this work establishes a unified framework for SHROOM-dependent morphogenetic control, highlighting therapeutic opportunities in developmental disorders and fibrosis through targeted kinase/phosphatase modulation.</p>

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Decoding the Evolution and Co-Phospho-Regulatory Networks of SHROOM Proteins

  • 期刊论文

  • 发表日期：

    2026年1月19日

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  • Noreen A Khan,
  • Athira C Rajeev,
  • Althaf Mahin,
  • Athira Perunelly Gopalakrishnan,
  • Prathik Basthikoppa Shivamurthy,
  • Nazah Naurah V,
  • Alimath Sambreena,
  • Rajesh Raju

摘要

The SHROOM protein family (SHROOM1-4) serves as master regulators of actomyosin contractility, apical-basal polarity, and tissue morphogenesis through conserved domains and extensive intrinsically disordered regions (IDRs) that harbour dynamic phosphorylation sites. This study explores their conserved evolutionary patterns, IDRs and integrates ~ 3,800 high-quality human phosphoproteomic datasets to decode co-phospho-regulatory networks of SHROOM1-4, identifying phosphosites per isoform, with few of the SHROOM1 and 3 predominant sites in domain and others clustered near ASD1/ASD2 boundaries. Co-occurrence heatmaps reveal tightly coupled multisite phosphorylation in SHROOM1/3 versus modular, inhibitory patterns in SHROOM2, while SHROOM4 exhibits minimal modification. Upstream kinases, 19 for SHROOM1, 9 for SHROOM2, 7 for SHROOM3 span MAPK, PI3K/AKT, and Rho pathways, with co-phosphorylated kinases, phosphatases, and binary interactors forming dense hubs integrating cytoskeletal, cell cycle, and transcriptional signaling. Dysregulation links SHROOM3 hypophosphorylation to neural tube defects and chronic kidney disease, SHROOM2 to cancer migration/EMT, and SHROOM4 mutations to intellectual disability. By mapping phospho-logic to functional outcomes, this work establishes a unified framework for SHROOM-dependent morphogenetic control, highlighting therapeutic opportunities in developmental disorders and fibrosis through targeted kinase/phosphatase modulation.