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Molecular and Cellular Biology, March 2004, p. 2499-2512, Vol. 24, No. 6
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.6.2499-2512.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Epidermal Growth Factor Activates m-Calpain (Calpain II), at Least in Part, by Extracellular Signal-Regulated Kinase-Mediated Phosphorylation

A. Glading ,1,{dagger},{ddagger} R. J. Bodnar,1,{dagger} I. J. Reynolds,2 H. Shiraha,1 L. Satish,1 D. A. Potter,3 H. C. Blair,1,4,5 and A. Wells1,5*

Departments of Pathology,1 Pharmacology,2 Physiology and Cell Biology, University of Pittsburgh,4 Pittsburgh Veterans Administration Medical Center, Pittsburgh, Pennsylvania 15261,5 Department of Dermatology, Indiana University Medical School, Indianapolis, Indiana3

Received 2 June 2003/ Returned for modification 29 July 2003/ Accepted 15 December 2003

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.

* Corresponding author. Mailing address: Department of Pathology, 713 Scaife, University of Pittsburgh, Pittsburgh, PA 15261. Phone: (412) 647-7813. Fax: (412) 647-8567. E-mail: wellsa{at}msx.upmc.edu.

{dagger} A.G. and R.J.B. contributed equally to this work.

{ddagger} Present address: Scripps Research Institute, La Jolla, Calif.

Molecular and Cellular Biology, March 2004, p. 2499-2512, Vol. 24, No. 6
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.6.2499-2512.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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