mCalpainandfriendsinCellmotility

The mammalian calpain gene family currently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. ( An excellent introduction to the calpain family can be found on a web site created by Valery Thompson http://ag.arizona.edu/calpains/index.html ) One of the most carefully studied functions of the calpains is the regulation of integrin-mediated cell migration. Calpains digests the links between the actin cytoskeleton and several focal adhesion complex proteins; talin, paxillin and focal adhesion kinase. The release from the focal adhesion complex facilitates migration. Calpestatin is an inhibitor expressed in most cells. Calpestatin binds the four inhibitory domains of calpain. Release from calpestatin does not activate calpain. Activation requires additional signaling, coactivators and an appropriate calcium concentration. During cell migration calpain1 (mu-calpain) acts at the leading edge as a response to integrin signals or calcium fluxuations due to the stretch activated calcium channels. Calpain1 cleaves the target proteins, talin, exzrin, paxillin and the cytoplasmic tail of the integrins B1(a) and B3(b) to release the adhesion and form new adhesions. Calpain2 (M-calpain) is believed to be membrane bound and functions at the trailing edge of the migrating cell to cleave the integrins in response to growth factor receptor signals. PKA functions to down regulate or inhibit calpain2 . Disease related notes: In Alzheimers disease, amyloid peptides interfere with calpain activity causing a mislocalization of cdk5. Deregulated cdk5 hyperphosphorylates tau promoting cell death in neurons (See Deregulation of CDK5 in Alzheimer’s Disease). Mutations in the muscle specific calpain p94 lead to Limb Girdle muscular dystrophy 2A (LGMD2A). Over activity of calpains due to elevated calcium leads to tissue damage in the heart and brain ( See reference Moldoveanu et al.)

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REFERENCES: Bialkowska K, Kulkarni S, Du X, Goll DE, Saido TC, Fox JE. Evidence that beta3 integrin-induced Rac activation involves the calpain-dependent formation of integrin clusters that are distinct from the focal complexes and focal adhesions that form as Rac and RhoA become active. J Cell Biol. 2000 Oct 30;151(3):685-96. Glading A, Lauffenburger DA, Wells A. Cutting to the chase: calpain proteases in cell motility. Trends Cell Biol. 2002 Jan;12(1):46-54. Review. Glading A, Uberall F, Keyse SM, Lauffenburger DA, Wells A. Membrane proximal ERK signaling is required for M-calpain activation downstream of epidermal growth factor receptor signaling. J Biol Chem. 2001 Jun 29;276(26):23341-8. Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA. Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol. 1997 Apr 21;137(2):481-92. Kulkarni S, Saido TC, Suzuki K, Fox JE. Calpain mediates integrin-induced signaling at a point upstream of Rho family members. J Biol Chem. 1999 Jul 23;274(30):21265-75. Moldoveanu T, Hosfield CM, Lim D, Elce JS, Jia Z, Davies PL. A Ca(2+) switch aligns the active site of calpain. Cell. 2002 Mar 8;108(5):649-60. Properties of the calpains. http://ag.arizona.edu/calpains/physical_properties.html