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Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing
Open accessAbstract
Accumulating evidence indicates that there is extensive crosstalk between integrins and TGF-beta signalling. TGF-beta affects integrin-mediated cell adhesion and migration by regulating the expression of integrins, their ligands and integrin-associated proteins. Conversely, several integrins directly control TGF-beta activation. In addition, a number of integrins can interfere with both Smad-dependent and Smad-independent TGF-beta signalling in different ways, including the regulation of the expression of TGF-beta signalling pathway components, the physical association of integrins with TGF-beta receptors and the modulation of downstream effectors. Reciprocal TGF-beta-integrin signalling is implicated in normal physiology, as well as in a variety of pathological processes including systemic sclerosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and cancer; thus, integrins could provide attractive therapeutic targets to interfere with TGF-beta signalling in these processes.
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“By disrupting mechanical force transmission between cells and the ECM, integrin inhibitors not only attenuate TGF-b activation but also modulate immune cell adhesion and migration, effectively dampening pro-fibrotic inflammation at its source (129).”
From The mechanotransduction-immune axis in organ fibrosis: dual regulatory mechanisms and translational therapeutic perspectives (2025) · cites this paper as [129]
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“integrins are known to activate TGF-β”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Margadant and Sonnenberg, 2010
In the citing paper
“Accumulating evidence indicates that a cross-talk between integrins and TGF-β exists, in particular to regulate fibrosis, wound healing, and cancer (Asano et al., 2005, Margadant and Sonnenberg, 2010).”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Margadant and Sonnenberg, 2010
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“In CAFs, αvβ6, αvβ3 and αvβ5 integrins have been shown to promote TGF-β1 activation, fibrosis and tumor progression(Jang & Beningo, 2019), indicating that targeting αv-integrins may interrupt the feedforward loop of matrix stiffening and TGFβ1 activation described several times in this review.”
BackgroundInfluentialCorneal myofibroblasts and fibrosis
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“Also likely important is the necessary activation of TGFβ that is produced as a precursor and must be activated by proteolysis and by interaction with integrins (Margadant and Sonnenberg, 2010; Dong et al., 2017).”
BackgroundRapid disorganization of mechanically interacting systems of mammary acini
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An αv‐RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities
Hatley, R. J. D., Macdonald, S. J. F., Slack, R. J., Le, J., Ludbrook, S. B., & Lukey, P. T. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201707948 · Cited by 132
Mechanobiology of annulus fibrosus and nucleus pulposus cells in intervertebral discs
Molladavoodi, S., McMorran, J. G., & Gregory, D. E. (2019) · Cell and Tissue Research · doi:10.1007/s00441-019-03136-1 · Cited by 134
Matrix‐dependent perturbation of TGFβ signaling and disease
Doyle, J. J., Gerber, E. E., & Dietz, H. C. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.05.027 · Cited by 130
Stromal POSTN induced by TGF-β1 facilitates the migration and invasion of ovarian cancer
Yue, H., Li, W., Chen, R., Wang, J., Lu, X., & Li, J. (2020) · Gynecologic Oncology · doi:10.1016/j.ygyno.2020.11.026 · Cited by 129
Shields, M. A., Dangi-Garimella, S. Y., Krantz, S. B., Bentrem, D. J., & Munshi, H. G. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.195628 · Cited by 124
Developmental pathways associated with cancer metastasis: Notch, Wnt, and Hedgehog
Kamdje, A. H. N., Kamga, P. T., Simo, R. T., Vecchio, L., Etet, P. F. S., Jm, M., Bassi, G., Lukong, K. E., Goel, R. K., Mbo, A. J., et al. (2017) · Cancer Biology and Medicine · doi:10.20892/j.issn.2095-3941.2016.0032 · Cited by 124
Soft tissue mechanotransduction in wound healing and fibrosis
Wong, V., Longaker, M. T., & Gurtner, G. C. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.09.010 · Cited by 123
CDK5 is essential for TGF-β1-induced epithelial-mesenchymal transition and breast cancer progression
Liang, Q. Y., Li, L., Zhang, J., Yang, L., Wang, L., Liu, D., Feng, J., Hou, P., Yao, R., Zhang, Y., et al. (2013) · Scientific Reports · doi:10.1038/srep02932 · Cited by 123
Zhou, Y., Hagood, J. S., Lu, B., Merryman, W. D., & Murphy-Ullrich, J. E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.126227 · Cited by 119
Reviewing the Regulators of COL1A1
Devos, H., Zoidakis, J., Roubelakis, M. G., Latosinska, A., & Vlahou, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241210004 · Cited by 119
“Our literature search highlighted transcription factors with existing evidence for direct binding to the upstream regions of COL1A1, namely Nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) [44] and Sma and Mad related protein 2/3 complex (Smad2/3 complex) in the context of the TGFβ signalling path…”
BackgroundKopf, J., Petersen, A., Duda, G. N., & Knaus, P. I. (2012) · BMC Biology · doi:10.1186/1741-7007-10-37 · Cited by 125
“Especially integrins crosstalk to TGFb and BMP signalling pathways [33].”
BackgroundArnold, K. M., Opdenaker, L. M., Flynn, D. C., & Sims‐Mourtada, J. (2015) · Cancer Growth and Metastasis · doi:10.4137/cgm.s11286 · Cited by 122
Irifuku, T., Doi, S., Sasaki, K., Doi, T., Nakashima, A., Ueno, T., Yamada, K., Arihiro, K., Kohno, N., & Masaki, T. (2015) · Kidney International · doi:10.1038/ki.2015.291 · Cited by 116
Kimura, R. H., Wang, L., Shen, B., Huo, L., Tummers, W. S. F. J., Filipp, F. V., Guo, H. H., Haywood, T., Abou‐Elkacem, L., Baratto, L., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11863-w · Cited by 120
Integrin-Mediated TGFβ Activation Modulates the Tumour Microenvironment
Brown, N. F., & Marshall, J. F. (2019) · Cancers · doi:10.3390/cancers11091221 · Cited by 116
Richardson, R. J., Metzger, M., Knyphausen, P., Ramezani, T., Slanchev, K., Kraus, C., Schmelzer, E., & Hammerschmidt, M. (2016) · Development · doi:10.1242/dev.130492 · Cited by 119
“…of focal adhesion proteins such as 5 1, 2 1, 3 1, v 5 and / or v 6 integrins that mediate cell movement via the dynamic binding of extracellular matrix (ECM) components such as fibronectin and collagen to cell surfaces (Margadant and Sonnenberg, 2010; Tsuruta et al., 2011).”
BackgroundThe role of integrins in TGFβ activation in the tumour stroma
Khan, Z. A., & Marshall, J. F. (2016) · Cell and Tissue Research · doi:10.1007/s00441-016-2474-y · Cited by 121
“…activates via phosphorylation the SMAD2 and SMAD3 transcription factors, which now can bind SMAD4 promoting their translocation to the nucleus in which the complex drives the transcription of a wide variety of genes, including the αv integrins (Levy and Hill 2005; Margadant and Sonnenberg 2010).”
BackgroundInfluentialModulation of the Tumor Microenvironment for Cancer Treatment: A Biomaterials Approach
Adjei, I. M., & Sharma, B. (2015) · Journal of Functional Biomaterials · doi:10.3390/jfb6010081 · Cited by 115
“Within tumors, the cytotoxic activity of M1 macrophages is inhibited by IL-4, IL-6, TGF-b1 and myocardiac depression factor secreted by cancer cells.”
BackgroundInfluentialRole of caveolin-1 in fibrotic diseases
Gvaramia, D., Blaauboer, M. E., Hanemaaijer, R., & Everts, V. E. (2013) · Matrix Biology · doi:10.1016/j.matbio.2013.03.005 · Cited by 112
van der Horst, G., van den Hoogen, C., Buijs, J. T., Cheung, H., Bloys, H., Pelger, R. C. M., Lorenzon, G., Heckmann, B., Feyen, J. H. M., Pujuguet, P., et al. (2011) · Neoplasia · doi:10.1593/neo.11122 · Cited by 110
α11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy
Talior‐Volodarsky, I., Connelly, K. A., Arora, P. D., Gullberg, D., & McCulloch, C. A. (2012) · Cardiovascular Research · doi:10.1093/cvr/cvs259 · Cited by 110
Enomoto, Y., Katsura, H., Fujimura, T., Ogata, A., Baba, S., Yamaoka, A., Kihara, M., Abe, T., Nishimura, O., Kadota, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40617-y · Cited by 123
Jiang, D., & Scharffetter‐Kochanek, K. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00697 · Cited by 110
“TGF-β signaling is the most important pathway that determines granulation tissue formation and wound healing outcome (Desmouliere et al., 1993; Margadant and Sonnenberg, 2010; Lichtman et al., 2016; Jiang and Rinkevich, 2020).”
BackgroundThe extracellular matrix of the dermis: flexible structures with dynamic functions
Krieg, T. M., & Aumailley, M. (2011) · Experimental Dermatology · doi:10.1111/j.1600-0625.2011.01313.x · Cited by 124
Epithelial polarity – Generating and integrating signals from the ECM with integrins
Manninen, A. (2015) · Experimental Cell Research · doi:10.1016/j.yexcr.2015.01.003 · Cited by 107
TGF beta −1, −2 and −3 in the modulation of fibrosis in the cornea and other organs
Wilson, S. E. (2021) · Experimental Eye Research · doi:10.1016/j.exer.2021.108594 · Cited by 113
Nowrin, K., Sohal, S. S., Peterson, G. M., Patel, R. P., & Walters, E. H. (2014) · Expert Review of Respiratory Medicine · doi:10.1586/17476348.2014.948853 · Cited by 99
“ILK, perhaps in combination with TGFb, induces the de novo expression of several integrins, such as a5b1, avb3 and avb6, which enhance the migration and invasion of carcinoma cells, particularly in conjunction with MMPs and fibronectin [89].”
Background
Metadata
- Authors
- Margadant, C., & Sonnenberg, A.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Sonnenberg, Arnoud
- Venue
- The EMBO Reports
- Published
- 2010-01-15
- Volume
- 11
- Issue
- 2
- Pages
- 97-105
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC2828749
- OpenAlex
- W2112195516
- Cited by
- 653
- References
- 81
- Citations by year
- 2026: 28 · 2025: 50 · 2024: 32 · 2023: 41 · 2022: 30 · 2021: 38 · 2020: 41 · 2019: 34 · 2018: 45 · 2017: 38 · 2016: 45 · 2015: 43 · 2014: 49 · 2013: 36 · 2012: 51
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- EMBO Reports (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Molecular Biology Organization
- Dystrophic Epidermolysis Bullosa Research Association
- KWF Kankerbestrijding
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- TGF-beta signaling, integrins, Smad signaling, TGF-beta receptor, cell adhesion, cell migration, fibrosis, systemic sclerosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, cancer, wound healing, therapeutic target
- MeSH terms
- Animals, Fibrosis, Humans, Models, Biological, Neoplasms, Wound Healing, Integrins, Transforming Growth Factor beta, Disease Progression, Receptor Cross-Talk
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