Related Experiment Video

Updated: Aug 14, 2025

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

13.2K

Protein tyrosine phosphatase PTPN2 regulates TGF-β signaling through Smad4 dephosphorylation

Sujing Shi1,2,3, Dewei Xu1,2,4, Shuchen Gu1,2,3

  • 1The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University Hangzhou 310058, Zhejiang, China.

American Journal of Cancer Research
|January 11, 2023
PubMed

Insights

Tyrosine phosphatase PTPN2 reactivates tumor-suppressive Transforming Growth Factor beta (TGF-β) signaling by dephosphorylating Smad4. This finding reveals PTPN2 as a potential tumor suppressor in ALK-positive cancers.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Transforming Growth Factor beta (TGF-β) is a key cytokine regulating cell functions, and its signaling pathway is often dysregulated in cancer.
  • Anaplastic Lymphoma Kinase (ALK) can phosphorylate Smad4, inhibiting TGF-β's tumor-suppressive effects in ALK-positive cancers.

Purpose of the Study:

  • To investigate the role of tyrosine phosphatase PTPN2 in regulating TGF-β signaling, particularly in the context of ALK-mediated inhibition.
  • To determine if PTPN2 can counteract the inhibitory effects of ALK on Smad4.

Main Methods:

  • In vitro and cell-based biochemical assays to assess PTPN2's interaction with and dephosphorylation of Smad4.
  • Overexpression studies of PTPN2 in ALK-positive cancer cells to evaluate its impact on TGF-β responses.
  • Treatment with Spermidine, a PTPN2 activator, to observe effects on TGF-β signaling.

Main Results:

  • PTPN2 directly binds to and dephosphorylates Smad4 at Tyr95, restoring its DNA-binding ability.
  • Overexpression of PTPN2 re-sensitized ALK-positive cancer cells to TGF-β's growth inhibitory and transcriptional effects.
  • Spermidine treatment mimicked PTPN2's effects, enhancing TGF-β-induced gene expression, apoptosis, and anti-proliferation.

Conclusions:

  • PTPN2 acts as a tumor suppressor by antagonizing the inhibitory tyrosine phosphorylation of Smad4.
  • PTPN2 is crucial for maintaining proper TGF-β growth inhibitory signaling, offering a potential therapeutic target in cancers with dysregulated TGF-β pathways.
Keywords:
ALKSmadspermidinetumor suppressortyrosine phosphorylation

More Related Videos

Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay11:38

Visualization and Quantification of TGFβ/BMP/SMAD Signaling under Different Fluid Shear Stress Conditions using Proximity-Ligation-Assay

Published on: September 14, 2021

3.4K
Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation09:40

Analysis of the c-KIT Ligand Promoter Using Chromatin Immunoprecipitation

Published on: June 27, 2017

7.8K

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
7.5K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
9.1K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.8K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.6K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.1K