Calpain function in the modulation of signal transduction molecules

Calpains are cytosolic cysteine proteases that are activated by a rise in intracellular Ca2+, and are believed to function in stimulating Ca2+ signaling on cell activation, leading the cell to differentiation, proliferation and death, In this review, we focus on the implication of calpains in signal transduction in molecules such as growth factors, T cell receptor, and integrin, Calpains are downstream molecules of hormone receptors, membrane-type tyrosine kinases and adhesion molecules, and proteolyze many signaling-related substrates. The substrates, protein kinase C (PKC), ( subunit of G-proteins, and protein tyrosine phosphatases, are cleaved at interdomain site(s) and their activities are sustained or upregulated, while the fragments of focal adhesion kinase and the tyrosine kinase src family lose their activity. In the integrin cascade, calpains are upstream molecules of the Rho GTPase family, Rac1 or RhoA, and allow the lamellipodia formation. The significant activation of calpain suggests that calpain activity is regulated not only by an increase in intracellular Ca2+, but also by signaling that include the PKC-, tyrosine kinase- or the adhesion molecule-derived cascade, We have summarized these interesting phenomena, and speculate on the function and location of calpain in the signaling cascades.