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Direct Activation of TACE-Mediated Ectodomain Shedding by p38 MAP Kinase Regulates EGF Receptor-Dependent Cell Proliferation
Open accessAbstract
Inflammatory stimuli activate ectodomain shedding of TNF-α, L-selectin and other transmembrane proteins. We show that p38 MAP kinase, which is activated in response to inflammatory or stress signals, directly activates TACE, a membrane-associated metalloprotease that effects shedding in response to growth factors and Erk MAP kinase activation. p38α MAP kinase interacts with the cytoplasmic domain of TACE, and phosphorylates it on Thr735, which is required for TACE-mediated ectodomain shedding. Activation of TACE by p38 MAP kinase results in the release of TGF-α family ligands, which activate EGF receptor signaling leading to enhanced cell proliferation. Conversely, depletion of p38α MAP kinase activity suppresses EGF receptor signaling and downstream Erk MAP kinase signaling, as well as autocrine EGF receptor-dependent proliferation. Autocrine EGF receptor activation through TACE-mediated ectodomain shedding intimately links inflammation and cancer progression, and may play a role in stress and conditions that relate to p38 MAP kinase activation.
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IKKβ Links Inflammation and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer
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Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis
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Cited by
Gheblawi, M., Wang, K., Viveiros, A., Nguyen, Q., Zhong, J.-C., Turner, A. J., Raizada, M. K., Grant, M. B., & Oudit, G. Y. (2020) · Circulation Research · doi:10.1161/circresaha.120.317015 · Cited by 1,882
Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure
Patel, V. B., Zhong, J.-C., Grant, M. B., & Oudit, G. Y. (2016) · Circulation Research · doi:10.1161/circresaha.116.307708 · Cited by 833
The shedding protease ADAM17: Physiology and pathophysiology
Zunke, F., & Rose-John, S. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.07.001 · Cited by 336
Thorp, E., Vaisar, T., Subramanian, M., Mautner, L., Blobel, C., & Tabas, I. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.263020 · Cited by 298
Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis
Cai, B., Dongiovanni, P., Corey, K. E., Wang, X., Shmarakov, I. O., Zheng, Z., Kasikara, C., Davra, V., Meroni, M., Chung, R. T., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.013 · Cited by 266
Metadata
- Authors
- Xu, P., & Derynck, R.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-02
- Volume
- 37
- Issue
- 4
- Pages
- 551-566
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2058062440
- Cited by
- 257
- References
- 4
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Xu, P., & Derynck, R. (2010). Direct Activation of TACE-Mediated Ectodomain Shedding by p38 MAP Kinase Regulates EGF Receptor-Dependent Cell Proliferation. Molecular Cell. https://doi.org/10.1016/j.molcel.2010.01.034
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