Relationship Between Pak-Mediated Cell Death and Stress-Activated Kinase Signaling in Breast Cancer
Abstract
P2L -ACTIVATED KINASES OR Pak's have been implicated in apoptosis as an upstream regulator with enhancing or suppressing influence and recognized as part of the cell death execution machinery. Here we show that a correlation exists in breast cancer cells between caspase- dependent cleavage of the Pak2 and activation of c-jun kinase. The mode of Pak kinase regulation has recently been identified. Small GTPases like Rac and Cdc42 or sphingoid-like lipids bind to Pak kinases, disrupt an intramolecular inhibitory interaction leading to increased phosphorylation of substrates. This intramolecular interaction is also disrupted by caspase-cleavage of Pak2. The autoinhibitory 83 amino acid region which interacts with the Pak kinase domain and inhibits its activity might allow us to specifically inhibit signaling pathways downstream of Pak and evaluate how the cell death process is affected. In a biochemical approach screening for substrates and possible mediators of cell death signaling components via Pak kinases we identified a guanine nucleotide exchange factor is phosphorylated by the Pak. In future studies we are going to evaluate the possibility of this GEF being a mediator of JNK and cell death signaling.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2000
- Accession Number
- ADB257398
Entities
People
- Frank T. Zenke
Organizations
- Scripps Research