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Epidermal Growth Factor Activates m-Calpain (Calpain II), at Least in Part, by Extracellular Signal-Regulated Kinase-Mediated Phosphorylation
Open accessAbstract
How m-calpain is activated in cells has challenged investigators because in vitro activation requires near-millimolar calcium. Previously, we demonstrated that m-calpain activation by growth factors requires extracellular signal-regulated kinase (ERK); this enables tail deadhesion and allows productive motility. We now show that ERK directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (EGF)-induced calpain activation in vitro and in vivo. Replacing the serine with alanine limits activation by EGF and subsequent cell deadhesion and motility. A construct with the serine converted to glutamic acid displays constitutive activity in vivo; expression of an estrogen receptor fusion construct produces a tamoxifen-sensitive enzyme. Interestingly, EGF-induced m-calpain activation occurs in the absence of increased intracellular calcium levels; EGF triggers calpain even in the presence of intracellular calcium chelators and in calcium-free media. These data provide evidence that m-calpain can be activated through the ERK cascade via direct phosphorylation and that this activation may occur in the absence of cytosolic calcium fluxes.
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“EGFR-mediated activation of epithelial proteases, particularly m-calpain through MAPK activity, contributed substantially to bacterial invasion across the tight junctions of the airway epithelium (27), demonstrated both in vitro and in vivo.”
From Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity (2011) · cites this paper as [27]
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Metadata
- Authors
- Glading, A., Bodnar, R. J., Reynolds, I. J., Shiraha, H., Satish, L., Potter, D. A., Blair, H. C., & Wells, A.
- Affiliations
- Departments of Pathology
- Pharmacology
- Indiana University School of Medicine (US)
- University of Pittsburgh (US)
- Veterans Health Administration (US)
- Corresponding author
- Wells, A.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-03-01
- Volume
- 24
- Issue
- 6
- Pages
- 2499-2512
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC355832
- OpenAlex
- W2153992286
- Cited by
- 271
- References
- 55
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 5 · 2017: 10 · 2016: 11 · 2015: 9 · 2014: 11 · 2013: 16 · 2012: 15
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Update notices
- correction (2004-07-01)
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Keywords
- m-calpain, epidermal growth factor, ERK signaling, protein phosphorylation, calpain activation, cell motility, calcium-independent activation
- MeSH terms
- Animals, Base Sequence, Binding Sites, Calcium, Calpain, Cell Line, Cell Movement, Enzyme Activation, Epidermal Growth Factor, Humans, Phosphorylation, Recombinant Proteins, Serine, Mutagenesis, Site-Directed, DNA, Complementary, Amino Acid Substitution, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Mice, In Vitro Techniques
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