2020-02-26 小河 ibioo.Com
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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抯 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.)