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Updated: Jan 29, 2026

Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
07:49

Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling

Published on: August 3, 2018

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PDZK1-interacting protein 1 (PDZK1IP1) traps Smad4 protein and suppresses transforming growth factor-β (TGF-β)

Souichi Ikeno1, Naoko Nakano1, Keigo Sano1

  • 1From the Laboratory of Biochemistry, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.

The Journal of Biological Chemistry
|February 6, 2019
PubMed

Insights

PDZK1-interacting protein 1 (PDZK1IP1) binds Smad4, inhibiting transforming growth factor-beta (TGF-β) and bone morphogenetic protein (BMP) signaling. This interaction suppresses tumor growth and enhances survival, revealing PDZK1IP1 as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Biology

Background:

  • Transforming growth factor-beta (TGF-β) signaling is crucial in human physiology but its dual role in tumorigenesis remains unclear.
  • TGF-β signaling pathways are tightly regulated to prevent dysregulation, particularly in cancer.

Purpose of the Study:

  • To investigate the role of PDZK1-interacting protein 1 (PDZK1IP1) in TGF-β signaling.
  • To elucidate the mechanism by which PDZK1IP1 modulates TGF-β and bone morphogenetic protein (BMP) pathways.

Main Methods:

  • Co-immunoprecipitation assays to confirm PDZK1IP1 and Smad4 interaction.
  • Reporter assays and Western blotting to assess pathway activity.
  • Functional assays including cell migration and proliferation assays.
  • In vivo xenograft tumor models to evaluate therapeutic potential.

Main Results:

  • PDZK1IP1 directly interacts with Smad4, inhibiting both TGF-β and BMP signaling pathways.
  • PDZK1IP1 functions by preventing R-Smad/Smad4 complex formation and retaining Smad4 in the cytoplasm.
  • PDZK1IP1 overexpression suppressed TGF-β-induced tumor cell migration, proliferation, and reduced tumor size in vivo.
  • PDZK1IP1 knockdown led to enhanced expression of TGF-β target genes, Smad7 and TMEPAI.

Conclusions:

  • PDZK1IP1 acts as a negative regulator of TGF-β/BMP signaling by interacting with Smad4.
  • PDZK1IP1 exhibits tumor-suppressive functions, decreasing tumor growth and improving survival rates.
  • Targeting PDZK1IP1-Smad4 interaction presents a potential therapeutic strategy for cancers where TGF-β signaling is oncogenic.
Keywords:
PDZK1-interacting protein 1 (PDZK1IP1)SMAD transcription factorSmad4bone morphogenetic protein (BMP)cell signalingreceptor protein serine/threonine kinasesignal transductiontranscriptiontransforming growth factor β (TGF-β)tumor

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