The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
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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“Even whether calpains are activated at the cell front during spreading or at the rear during detachment has only been addressed indirectly (3, 26, 41, 43, 45).”
BackgroundCutting to the chase: calpain proteases in cell motility
Glading, A., Lauffenburger, D. A., & Wells, A. H. (2002) · Trends in Cell Biology · doi:10.1016/s0962-8924(01)02179-1 · Cited by 388
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Yoon, S., & Seger, R. (2006) · Growth Factors · doi:10.1080/02699050500284218 · Cited by 1,331
MAP kinases and cell migration
Huang, C., Jacobson, K., & Schaller, M. D. (2004) · Journal of Cell Science · doi:10.1242/jcs.01481 · Cited by 1,089
The role of focal-adhesion kinase in cancer — a new therapeutic opportunity
McLean, G. W., Carragher, N. O., Avizienyte, E., EVANS, J., Brunton, V. G., & Frame, M. C. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1647 · Cited by 1,049
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RAF-MEK-ERK pathway in cancer evolution and treatment
Ullah, R., Yin, Q., Snell, A. H., & Wan, L. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.05.010 · Cited by 553
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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