Epidermal growth factor activates m-calpain (calpain II), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.

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.
Mesh Terms:
Amino Acid Substitution, Animals, Base Sequence, Binding Sites, Calcium, Calpain, Cell Line, Cell Movement, DNA, Complementary, Enzyme Activation, Epidermal Growth Factor, Humans, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinases, Mutagenesis, Site-Directed, Phosphorylation, Recombinant Proteins, Serine
Mol. Cell. Biol.
Date: Mar. 01, 2004
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