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<p>The protein phosphatase 1&#xa0;(PP1) regulatory subunit, TGF-β inhibited membrane-associated protein (TIMAP), is highly expressed in neuronal cells, yet its role in regulating PP1 activity remains poorly understood. To investigate this, TIMAP was stably depleted in SH-SY5Y human neuroblastoma cells. Transcriptomic analysis identified 614 differentially expressed genes upon TIMAP depletion, with gene ontology analysis highlighting significant disruption of the bone morphogenetic protein (BMP) signaling pathway. Functional studies showed that TIMAP depletion reduced SMAD1 protein levels following stimulation with BMP7. While the activation-dependent C-terminal phosphorylation of SMAD1/5/8 remained unaffected, its nuclear translocation was strongly impaired. This defect is caused by the accelerated proteasomal degradation of the cytoplasmic SMAD1 pool, which limits the amount of protein available for nuclear import. Our data demonstrate that TIMAP directs PP1 to the SMAD1 linker region to control phosphorylation dynamics. In the absence of TIMAP, elevated Ser206 phosphorylation in the SMAD1 linker region recruits the ubiquitin ligase SMURF1, leading to increased SMAD1 ubiquitination and clearance. These findings reveal that TIMAP maintains the integrity of BMP signaling by targeting PP1 to dephosphorylate regulatory sites, thereby preventing ubiquitin-mediated degradation and promoting effective nuclear functions.</p>

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TIMAP depletion impairs BMP signaling by accelerating SMURF1-mediated SMAD degradation in neuroblastoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月31日

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  • Márton Fonódi,
  • Bálint Bécsi,
  • Krisztina Tar,
  • Anita Boratkó

摘要

The protein phosphatase 1 (PP1) regulatory subunit, TGF-β inhibited membrane-associated protein (TIMAP), is highly expressed in neuronal cells, yet its role in regulating PP1 activity remains poorly understood. To investigate this, TIMAP was stably depleted in SH-SY5Y human neuroblastoma cells. Transcriptomic analysis identified 614 differentially expressed genes upon TIMAP depletion, with gene ontology analysis highlighting significant disruption of the bone morphogenetic protein (BMP) signaling pathway. Functional studies showed that TIMAP depletion reduced SMAD1 protein levels following stimulation with BMP7. While the activation-dependent C-terminal phosphorylation of SMAD1/5/8 remained unaffected, its nuclear translocation was strongly impaired. This defect is caused by the accelerated proteasomal degradation of the cytoplasmic SMAD1 pool, which limits the amount of protein available for nuclear import. Our data demonstrate that TIMAP directs PP1 to the SMAD1 linker region to control phosphorylation dynamics. In the absence of TIMAP, elevated Ser206 phosphorylation in the SMAD1 linker region recruits the ubiquitin ligase SMURF1, leading to increased SMAD1 ubiquitination and clearance. These findings reveal that TIMAP maintains the integrity of BMP signaling by targeting PP1 to dephosphorylate regulatory sites, thereby preventing ubiquitin-mediated degradation and promoting effective nuclear functions.