TGF-β-induced cell motility requires downregulation of ARHGAPs to sustain Rac1 activity.

Abstract

Transforming growth factor-β (TGF-β) signaling promotes cancer progression. In particular, the epithelial-mesenchymal transition (EMT) induced by TGF-β is considered crucial to the malignant phenotype of cancer cells. Here, we report that the EMT-associated cellular responses induced by TGF-β are mediated by distinct signaling pathways that diverge at Smad3. By expressing chimeric Smad1/Smad3 proteins in SMAD3 knockout A549 cells, we found that the β4 region in the Smad3 MH1 domain is essential for TGF-β-induced cell motility, but is not essential for other EMT-associated responses including epithelial marker downregulation. TGF-β was previously reported to enhance cell motility by activating Rac1 via phosphoinositide 3-kinase. Intriguingly, TGF-β-dependent signaling mediated by Smad3's β4 region causes the downregulation of multiple mRNAs that encode GTPase activating proteins that target Rac1 (ARHGAPs), thereby attenuating Rac1 inactivation. Therefore, two independent pathways downstream of TGF-β type I receptor contribute cooperatively to sustained Rac1 activation, thereby leading to enhanced cell motility.

• Authors: Mitsuyoshi Motizuki, Daizo Koinuma, Takashi Yokoyama, Yuka Itoh, Chiho Omata, Kohei Miyazono, Masao Saitoh, Keiji Miyazawa
• Journal: The Journal of biological chemistry (J Biol Chem) 2021 Jan-Jun Vol. 296 Pg. 100545 ISSN: 1083-351X [Electronic] United States
• PMID: 33741342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• ARHGAP1 protein, human
• GTPase-Activating Proteins
• RAC1 protein, human
• SMAD3 protein, human
• Smad3 Protein
• Transforming Growth Factor beta
• rac1 GTP-Binding Protein

Topics

• A549 Cells
• Cell Movement
• Epithelial-Mesenchymal Transition
• GTPase-Activating Proteins (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation
• Smad3 Protein (genetics, metabolism)
• Transforming Growth Factor beta (pharmacology)
• rac1 GTP-Binding Protein (genetics, metabolism)