1. Academic Validation
  2. Phosphoinositide-binding activity of Smad2 is essential for its function in TGF-β signaling

Phosphoinositide-binding activity of Smad2 is essential for its function in TGF-β signaling

  • J Biol Chem. 2021 Nov;297(5):101303. doi: 10.1016/j.jbc.2021.101303.
Pawanthi Buwaneka 1 Arthur Ralko 1 Sukhamoy Gorai 1 Ha Pham 1 Wonhwa Cho 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
  • 2 Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA. Electronic address: wcho@uic.edu.
Abstract

As a central player in the canonical TGF-β signaling pathway, SMAD2 transmits the activation of TGF-β receptors at the plasma membrane (PM) to transcriptional regulation in the nucleus. Although it has been well established that binding of TGF-β to its receptors leads to the recruitment and activation of SMAD2, the spatiotemporal mechanism by which SMAD2 is recruited to the activated TGF-β Receptor complex and activated is not fully understood. Here we show that SMAD2 selectively and tightly binds phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) in the PM. The PI(4,5)P2-binding site is located in the MH2 domain that is involved in interaction with the TGF-β Receptor I that transduces TGF-β-receptor binding to downstream signaling proteins. Quantitative optical imaging analyses show that PM recruitment of SMAD2 is triggered by its interaction with PI(4,5)P2 that is locally enriched near the activated TGF-β Receptor complex, leading to its binding to the TGF-β Receptor I. The PI(4,5)P2-binding activity of SMAD2 is essential for the TGF-β-stimulated phosphorylation, nuclear transport, and transcriptional activity of SMAD2. Structural comparison of all Smad MH2 domains suggests that membrane lipids may also interact with other Smad proteins and regulate their function in diverse TGF-β-mediated biological processes.

Keywords

MH2 domain; PI(4,5)P((2)); Smad2; TGF-b; TGF-b receptor; membrane-protein interaction; plasma membrane targeting.

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