previous network
next network
Calpain-1 and Cdk5 interplay in neurons and cell death.
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
This network depicts a complex interplay between proline-directed, serine/threonine cyclin-dependent kinase 5 (cdk5) and a Ca2+-dependent protease calpain, which is involved in a plethora of normal and pathological processes in the mammalian CNS.
Cdk5, a multi-functional kinase, and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease. Conversion of p35 to p25 causes prolonged activation and miss-localization of cdk5 and hyperphosphorylation of tau, leading to the formation of paired helical filaments and promoting apoptosis. In vitro, calpain-1 directly cleaves p35 and specific inhibitors of calpain-1 (capn1) effectively inhibit the calcium-induced cleavage. Application of the amyloid-beta peptide (A beta) could induce the conversion of p35 to p25 in primary cortical neurons. Inhibition of cdk5 or calpain activity reduces cell death in A beta-treated cortical neurons. These observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease. Deregulation of Cdk5 by the truncated co-activator p29, also contributes to neurodegeneration by altering the phosphorylation state of proteins and, possibly, through the induction of cell cycle regulators, which may lead to amyotrophic lateral sclerosis.
In addition to the proteolysis of cdk5, proteolysis of the NMDA receptor subunit NR2B is a well characterized calpain-dependent process. Cdk5/p25 markedly enhances calpain-mediated cleavage of the NR2B C terminus in vitro. Cdk5 could affect calpain-mediated cleavage of NR2B via either phosphorylation or direct binding. However, Cdk5 phosphorylates neither calpain nor NR2B in vitro, and it activates calpain in the absence of Mg2+ and ATP. Thus, cleavage enhancement is independent of kinase activity. On the other hand, NR2B, Cdk5, p35 and calpain coimmunoprecipitate with one another; and with PSD-95, a scaffolding molecule enriched at glutamatergic synapses that is thought to may maintain a balance between excitation and inhibition in the brain.
A third proteolytic cleavage event by calpain is that of the Bcl-2 family member Bax into an 18-kDa protein, an early event in the induction of apoptosis. It is not known whether and/or how the proteolytic cleavage of Bax by calpain affects its known cell death-promoting function in neuronal cells.
Overall, aberrant calpain activation is a key mediator of neuronal death. The distinct mechanisms whereby calpain is activated in each of these paradigms of cell death remain to be thoroughly determined in the future.
Cdk5, a multi-functional kinase, and its neuron-specific activator p35 are required for neurite outgrowth and cortical lamination. Proteolytic cleavage of p35 produces p25, which accumulates in the brains of patients with Alzheimer's disease. Conversion of p35 to p25 causes prolonged activation and miss-localization of cdk5 and hyperphosphorylation of tau, leading to the formation of paired helical filaments and promoting apoptosis. In vitro, calpain-1 directly cleaves p35 and specific inhibitors of calpain-1 (capn1) effectively inhibit the calcium-induced cleavage. Application of the amyloid-beta peptide (A beta) could induce the conversion of p35 to p25 in primary cortical neurons. Inhibition of cdk5 or calpain activity reduces cell death in A beta-treated cortical neurons. These observations indicate that cleavage of p35 to p25 by calpain may be involved in the pathogenesis of Alzheimer's disease. Deregulation of Cdk5 by the truncated co-activator p29, also contributes to neurodegeneration by altering the phosphorylation state of proteins and, possibly, through the induction of cell cycle regulators, which may lead to amyotrophic lateral sclerosis.
In addition to the proteolysis of cdk5, proteolysis of the NMDA receptor subunit NR2B is a well characterized calpain-dependent process. Cdk5/p25 markedly enhances calpain-mediated cleavage of the NR2B C terminus in vitro. Cdk5 could affect calpain-mediated cleavage of NR2B via either phosphorylation or direct binding. However, Cdk5 phosphorylates neither calpain nor NR2B in vitro, and it activates calpain in the absence of Mg2+ and ATP. Thus, cleavage enhancement is independent of kinase activity. On the other hand, NR2B, Cdk5, p35 and calpain coimmunoprecipitate with one another; and with PSD-95, a scaffolding molecule enriched at glutamatergic synapses that is thought to may maintain a balance between excitation and inhibition in the brain.
A third proteolytic cleavage event by calpain is that of the Bcl-2 family member Bax into an 18-kDa protein, an early event in the induction of apoptosis. It is not known whether and/or how the proteolytic cleavage of Bax by calpain affects its known cell death-promoting function in neuronal cells.
Overall, aberrant calpain activation is a key mediator of neuronal death. The distinct mechanisms whereby calpain is activated in each of these paradigms of cell death remain to be thoroughly determined in the future.
Other Networks
Below are links to NCBI by PMID supporting this network.
© The PMAP Web Site is managed by The Center on Proteolytic Pathways at the Burnham Institute for Medical Research through a grant from the NIH Roadmap.
Copyright 2008. All rights reserved.
The Burnham Institute for Medical Research 10901 N. Torrey Pines Rd., La Jolla, CA 92037.
With problems, comments, or suggestions please contact: pmap_info@burnham.org