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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
Grynkiewicz, G., Poenie, M., & Tsien, R. Y. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)83641-4 · Cited by 21,562
Calcium-activated neutral protease (calpain) system: structure, function, and regulation.
Croall, D. E., & Demartino, G. (1991) · Physiological Reviews · doi:10.1152/physrev.1991.71.3.813 · Cited by 837
Littlewood, T. D., Hancock, D. C., Danielian, P. S., Parker, M. G., & Evan, G. I. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.10.1686 · Cited by 782
Structure and physiological function of calpains
Sorimachi, H., Ishiura, S., & Suzuki, K. (1997) · Biochemical Journal · doi:10.1042/bj3280721 · Cited by 706
Hirose, K., Kadowaki, S., Tanabe, M., Takeshima, H., & Iino, M. (1999) · Science · doi:10.1126/science.284.5419.1527 · Cited by 512
The organisation and functions of local Ca2+ signals
Bootman, M. D., Lipp, P., & Berridge, M. J. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.12.2213 · Cited by 449
Regulation of Cell Migration by the Calcium-dependent Protease Calpain
Huttenlocher, A., Palecek, S. P., Lu, Q., Zhang, W., Mellgren, R. L., Lauffenburger, D. A., Ginsberg, M. H., & Horwitz, A. F. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.52.32719 · Cited by 390 · cited 2×
“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
Self-citationStrobl, S., Fernandez-Catalan, C., Braun, M., Huber, R., Masumoto, H., Nakagawa, K., Irie, A., Sorimachi, H., Bourenkov, G. P., Bartunik, H. D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.2.588 · Cited by 366
Hosfield, C. M., Elce, J. S., Davies, P. L., & Jia, Z. (1999) · The EMBO Journal · doi:10.1093/emboj/18.24.6880 · Cited by 360
Research works printed but not linked: 2
- Guttmann R. P., 2000, Methods Mol. Biol., 144, 143
- Shiraha H., 1999, J. Cell Biol., 146, 243
Cited by
Sorted by citations
Items 201–271 of 271
Duquette, P. M., & Lamarche‐Vane, N. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14837 · Cited by 10
Yang, G., Liang, B., Zhu, J. Y., & Luo, Z. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.196568 · Cited by 10
Critchley, D. R. (2009) · Nature Cell Biology · doi:10.1038/ncb0509-538 · Cited by 10
The neuronal transcription factor MEIS2 is a calpain-2 protease target
Müller, T., Reichlmeir, M., Hau, A., Wittig, I., & Schulte, D. (2024) · Journal of Cell Science · doi:10.1242/jcs.261482 · Cited by 9
Regulation of calpain B from Drosophila melanogaster by phosphorylation
Kovács, L., Alexa, A., Klement, É., Kókai, E., Tantos, Á., Gógl, G., Sperka, T., Medzihradszky, K. F., Tőzsér, J., Dombrádi, V., et al. (2009) · FEBS Journal · doi:10.1111/j.1742-4658.2009.07198.x · Cited by 9
Maki, M. (2019) · Bioscience Biotechnology and Biochemistry · doi:10.1080/09168451.2019.1700099 · Cited by 9
Methods and computational tools to study eukaryotic cell migration in vitro
Toscano, E., Cimmino, E., Pennacchio, F. A., Riccio, P., Poli, A., Liu, Y., Maiuri, P., Sepe, L., & Paolella, G. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1385991 · Cited by 8
Partial autolysis of μ/m‐calpain during post mortem aging of chicken muscle
Zhao, L., Jiang, N., Li, M., Huang, M., & Zhou, G. (2016) · Animal Science Journal · doi:10.1111/asj.12602 · Cited by 8
Multi-phasic bi-directional chemotactic responses of the growth cone
Naoki, H., Nishiyama, M., Togashi, K., Igarashi, Y., Hong, K., & Ishii, S. (2016) · Scientific Reports · doi:10.1038/srep36256 · Cited by 8
Na, J., Zhang, L., Zheng, L., Jiang, J., Shi, Q., Li, C., & Fan, Y. (2022) · Cytotechnology · doi:10.1007/s10616-022-00533-3 · Cited by 8
Zhou, R., Wu, J. H., Gong, Y. P., Guo, Y., & Xing, H. Y. (2014) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2013.12.007 · Cited by 8
Fan, X., Zhang, Q., You, C., Qian, Y., Gao, J., Liu, P., Chen, H., Song, H., Chen, Y., Chen, K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093642 · Cited by 8
Calpain in Traumatic Brain Injury: From Cinderella to Central Player
Schallerer, C., Neuschmid, S., Ehrlich, B. E., & McGuone, D. (2025) · Cells · doi:10.3390/cells14161253 · Cited by 7
Suzuki, S., Murotomi, K., Nakajima, Y., Kawai, K., Ohta, K., Warita, K., Miki, T., & Takeuchi, Y. (2014) · ACS Synthetic Biology · doi:10.1021/sb500070c · Cited by 7
Prime editing in mice with an engineered pegRNA
Salem, A. R., Bryant, W. B., Doja, J., Griffin, S. H., Shi, X., Han, W., Su, Y., Verin, A. D., & Miano, J. M. (2023) · Vascular Pharmacology · doi:10.1016/j.vph.2023.107269 · Cited by 7
Regulation of cell polarity by controlled proteolytic systems
Bórquez, D. A., & González-Billault, C. E. (2011) · Biological Research · doi:10.4067/s0716-97602011000100005 · Cited by 7
Ge, X.-Y., Zhu, T., Yao, M.-Z., Liu, H., Wu, Q. H., Qiao, J., Zhang, W., & Hu, C.-P. (2021) · BioMed Research International · doi:10.1155/2021/2202888 · Cited by 6
The role of calcium-calpain pathway in hyperthermia
Enomoto, A., & Fukasawa, T. (2022) · Frontiers in Molecular Medicine · doi:10.3389/fmmed.2022.1005258 · Cited by 6
Atrial Calpains: Mediators of Atrialmyopathies in Atrial Fibrillation.
Bukowska, A., Lendeckel, U., & Goette, A. (2014) · PubMed Central · doi:10.4022/jafib.1021 · Cited by 6
The Role of Calpains in Regulating Synaptic Transmission
Karpenko, M. N., & Tikhomirova, M. S. (2015) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-015-0169-6 · Cited by 6
The tyrosine phosphatase HD-PTP (PTPN23) is degraded by calpains in a calcium-dependent manner
Castiglioni, S., & Maier, J. A. M. (2012) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2012.04.024 · Cited by 6
SUMO modification modulates the activity of calpain-2
Wang, H., Huang, Y., Ho, C.-C., Jeng, J., & Shih, H. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.04.152 · Cited by 6
Zhou, W. (2006) · D-Scholarship@Pitt (University of Pittsburgh) · Cited by 7
Langlois, B., Martin, J., Schneider, C., Hachet, C., Terryn, C., Rioult, D., Martiny, L., Thérêt, L., Salesse, S., & Dedieu, S. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.981927 · Cited by 5
The Cytoskeletal Connection: Understanding Adaptor Proteins
Ziegler, W. H. (2010) · Translational research in biomedicine · doi:10.1159/000274481 · Cited by 5
Kishore, R. (2014) · Journal of Molecular and Genetic Medicine · doi:10.4172/1747-0862.1000167 · Cited by 5
Motility in Tumor Invasion and Metastasis — An Overview
Wells, A. H. (2006) · Springer eBooks · doi:10.1007/1-4020-4009-1_1 · Cited by 5
Self-citationThe Calpain Proteolytic System
Baudry, M., Su, W., & Bi, X. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-821618-7.00223-6 · Cited by 5
Analysis of the structure of calpain-10 and its interaction with the protease inhibitor SNJ-1715
da Silva, R. C., Alencar, N., Alves, C. N., & Lameira, J. (2013) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2013.07.010 · Cited by 4
Expression of typical calpains in mouse molar
Matsunaga, T., Yamamoto, G., & TACHIKAWA, T. (2009) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2009.07.002 · Cited by 4
Bušek, P., Převorovský, M., Krepela, E., & Šedo, A. (2014) · Springer eBooks · doi:10.1007/978-3-7091-1431-5_12 · Cited by 4
CHAPTER 78 – Integrin Signaling: Cell Migration, Proliferation, and Survival
Parsons, J. T., Slack‐Davis, J. K., Tilghman, R. W., Iwanicki, M., & Martin, K. H. (2003) · Academic Press eBooks · Cited by 4
Спирина, Л. В., & Кондакова, И. В. (2010) · Russian Journal of Oncology · doi:10.17816/onco39886 · Cited by 4
Parsons, J. T., Slack‐Davis, J. K., Tilghman, R. W., Iwanicki, M., & Martin, K. H. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00066-8 · Cited by 4
Cell Motility in Prostate Tumor Invasion and Metastasis
Kharait, S., Tran, K., Yates, C. C., & Wells, A. H. (2006) · Springer eBooks · doi:10.1007/1-4020-4009-1_13 · Cited by 4
Self-citationRamos‐Miguel, A., Sánchez‐Blázquez, P., & Garcı́a-Sevilla, J. A. (2021) · Pharmacological Reports · doi:10.1007/s43440-021-00240-4 · Cited by 3
Kurow, O., Nuwayhid, R., Stock, P., Steinert, M., Langer, S., Krämer, S., & Metelmann, I. (2023) · Bioengineering · doi:10.3390/bioengineering10050537 · Cited by 3
Rasl, J., Čáslavský, J., Grušanović, J., Chvalová, V., Kosla, J., Adamec, J., Groušl, T., Klímová, Z., & Vomastek, T. (2024) · Cellular Signalling · doi:10.1016/j.cellsig.2024.111295 · Cited by 2
Roles of Membrane-type 1 Matrix Metalloproteinase in Tumor Invasion and Progression
Takino, T. (2007) · Journal of Oral Biosciences · doi:10.1016/s1349-0079(07)80005-3 · Cited by 2
Cellular regulators of myoblast migration and myogenesis
Dimchev, G. A. (2026) · e-space (Manchester Metropolitan University) · doi:10.83056/mmu.32434632 · Cited by 2
Noncanonical altPIDD1 protein: unveiling the true major translational output of the PIDD1 gene
Comtois, F., Jacques, J., Métayer, L., Ouedraogo, W. Y. D. D., Ouangraoua, A., Denault, J., & Roucou, X. (2024) · Life Science Alliance · doi:10.26508/lsa.202402910 · Cited by 1
MAP3K1: A Multifunctional Kinase at the Crossroads of Cancer Progression and Tumor Suppression
Umeta, L. T., & Natarajan, A. (2026) · Cells · doi:10.3390/cells15070604 · Cited by 1
Molecular Markers of Kidney Cancer Progression, Association with Efficiency of Pazopanib Therapy
Спирина, Л. В., Usynin, E. A., Кондакова, И. В., Yurmazov, Z. A., & Slonimskaya, E. M. (2015) · Journal of Biomedical Science and Engineering · doi:10.4236/jbise.2015.811072 · Cited by 1
The aminopeptidase B (Ap-B) is phosphorylated in HEK293 cells
Adicéam, E., Devakumaran, S., Cadel, S., Foulon, T., & Ghélis, T. (2022) · Biochimie · doi:10.1016/j.biochi.2022.07.010 · Cited by 1
WNT AND BETA-CATENIN IN HEPATIC DIFFERENTIATION: WHICH WAY DOES THE WNT BLOW?
Lade, A. G. (2011) · D-Scholarship@Pitt (University of Pittsburgh) · Cited by 1
Mechanism of the Effect of Protein Phosphorylation on Calpain Activity
Zhang, D., Li, X., Chen, L., Hou, C., & Wang, Z. (2020) · Springer eBooks · doi:10.1007/978-981-15-9441-0_8 · Cited by 1
Post-translational regulation of KCC2 in the rat hippocampus
Ahmad, F. (2012) · Työväentutkimus Vuosikirja · Cited by 1
Drug combinations targeting FAK and MEK overcomes tumour heterogeneity in glioblastomaPreprint
Furqan, M., Elliott, R. J. R., Nagle, P. W., Dawson, J. C., Masalmeh, R. H. A., Garcia, V. A., Munro, A. F., Drake, C., Morrison, G. M., Pollard, S. M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.26.625442 · Cited by 1
19 Calpain proteases in prostate carcinoma
Wells, A. H., Kharait, S., Yates, C. C., & Satish, L. (2002) · Handbook of immunohistochemistry and in situ hybridization of human carcinomas · doi:10.1016/s1874-5784(02)80051-4
Self-citationModeling and targeting signal transduction pathways governing cell migration
Kharait, S. (2006) · D-Scholarship@Pitt (University of Pittsburgh)
Studies on Memo, an important ErbB2 receptor-mediated component of the cellular migratory machinery
Meira, M. (2009) · edoc (University of Basel) · doi:10.5451/unibas-004780709
The Effect of Lethal Toxin on the Respiratory Epithelium.
Lehmann, M. D. (2008) · doi:10.5282/edoc.8250
Current and Future Therapeutic Targets of the Tumour-Host Microenvironment
Kassis, J., Alejandro, E., Virador, V. M., & Kohn, E. (2005) · Springer eBooks · doi:10.1007/1-4020-3414-8_20
Asymmetric Localization of Calpain 2 during Neutrophil
Nuzzi, P. A., Senetar, M. A., & Anna Huttenlocher, A. (2007)
Relaying the Signal During Myogenesis: Intracellular Mediators and Targets
O’Connor, R. S., & Pavlath, G. K. (2008) · Springer eBooks · doi:10.1007/978-1-4020-6768-6_7
CALPAIN 2 ACTIVATION, AUTOLYSIS, AND SUBUNIT DISSOCIATION
Chou, J. S. (2010) · QSpace (Queen's University Library)
Non-apoptotic roles of caspase-8 and caspase-2
Helfer, B. M. (2008) · doi:10.33915/etd.4380
Wells, A. H., & Leloup, L. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-374145-5.00126-1
Self-citationAuricchio, F., & Migliaccio, A. (2010) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.1764972.1288070
Prime Editing in Mice with an Engineered pegRNAPreprint
Ghanam, A. R., Bryant, W. B., Doja, J., Griffin, S. H., Shi, X., Han, W., Su, Y., Verin, A. D., & Miano, J. M. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4581217
Hara, H., Goshima, H., Hoshino, D., & Honda, M. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152896
Synthetic Peptide Ligand Mimetics and Tumor Cell Motility
Sroka, T. C. (2005) · UA Campus Repository (The University of Arizona)
Rôle et modes d'action de la Tétraspanine 8 dans l'invasion précoce du mélanome cutané
Kharbili, M. E. (2013) · theses.fr (ABES) · doi:10.70675/3e596898z95f7z4eb2za2aaz44ee31529d70
ERK-mediated phosphorylation modulates the autolytic processing of the cysteine protease CAPN3
Hisatsune, C., Shinkai‐Ouchi, F., Shindo, M., Hata, S., & Ono, Y. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113638
Stetler, R. A. (2005) · D-Scholarship@Pitt (University of Pittsburgh)
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
