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First published online August 29, 2005
doi: 10.1242/10.1242/jcs.02562

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Regulating cell migration: calpains make the cut

¹ Program in Cellular and Molecular Biology, University of Wisconsin, Madison, WI 53705, USA
² Departments of Pediatrics and Pharmacology, University of Wisconsin, Madison, WI 53705, USA

View larger version (17K): [in a new window]   Fig. 1. Schematic representation of the domain architecture of the classical calpains. The 80 kDa large subunits can be divided into four domains, plus a short linker that might be important for transducing conformational changes throughout the molecule upon calcium binding (T). The N-terminal -helix makes up domain I, which interacts with the small subunits before undergoing intermolecular autolysis on activation. Protease activity is contained within domain II, which is further divided into subdomains (IIa and IIb) that make up the two halves of the active site. Domain III comprises a C2-like domain that harbors sites for phosphorylation and phospholipid binding. Five consecutive EF-hand motifs make up domain IV and contribute to the calcium binding of the large subunits and to dimerization with the small subunits. Domain VI of the small subunits has a similar arrangement; the first four EF hands participate in calcium binding and the last motif interacts with the large subunit. The small subunits also contain a highly flexible, glycine-rich region called domain V. Calpain 1 and calpain 2 large subunits are phosphorylated at several sites in domains I-III; some of these residues are conserved and some are isoform specific.

View larger version (50K): [in a new window]   Fig. 2. (A) Some of the mechanisms involved in regulating calpain activity. (B) Possible pathway for growth-factor-induced, calpain-mediated cell migration. Binding of epidermal growth factor (EGF) to its receptor (EGFR) activates a MAP kinase cascade that eventually activates ERK. The scaffolding function of FAK brings ERK and calpain 2 into a complex, resulting in phosphorylation of calpain 2. This ERK-mediated phosphorylation leads to activation of calpain 2, which can be counteracted by phosphorylation of calpain 2 by PKA. Active calpain 2 can then cleave talin 1, leading to adhesion complex turnover and cell migration.

View larger version (27K): [in a new window]   Fig. 3. Motility-related processes known to be affected by calpains and the substrates or binding partners acting as effectors. Calpain 2 can cleave adhesion complex proteins such as FAK, paxillin and talin 1, possibly resulting in integrin activation, adhesion complex turnover or detachment of the cell rear. Proteolysis of the actin-regulating protein cortactin might lead to inhibition of membrane protrusion. Cleavage of integrin ß-tails might be important for the formation of small integrin clusters during the early stages of cell spreading, whereas proteolysis of the small GTPase RhoA negatively regulates cell spreading. Interaction of PIX with calpain small subunit 1 (CSS1) can also mediate cell spreading. Proteolysis of the adaptor protein MARCKS might also regulate cell migration in myoblasts, possibly by promoting adhesion formation. The isoforms required for proteolysis of integrins, RhoA and MARCKS remain to be determined, as do the processes affected by proteolysis of nearly 100 other calpain substrates.