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Published on: July 17, 2019
Kinase suppressor of Ras is ceramide-activated protein kinase
1Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cell
|April 4, 1997
Summary
Kinase suppressor of Ras (KSR) is identified as ceramide-activated protein (CAP) kinase. KSR mediates transmembrane signaling via the sphingomyelin pathway, activating Raf-1 and initiating TNF alpha signaling.
Area of Science:
- Cellular signaling pathways
- Molecular biology
- Signal transduction
Background:
- Ceramide-activated protein (CAP) kinase mediates transmembrane signaling through the sphingomyelin pathway.
- CAP kinase initiates proinflammatory Tumor Necrosis Factor alpha (TNF alpha) action by phosphorylating and activating Raf-1.
Purpose of the Study:
- To identify the molecular identity of CAP kinase.
- To investigate the role of Kinase Suppressor of Ras (KSR) in the sphingomyelin pathway and TNF alpha signaling.
Main Methods:
- Genetic identification of KSR in Caenorhabditis elegans and Drosophila.
- Biochemical characterization of mouse KSR, including autophosphorylation and membrane-binding properties.
- Analysis of KSR's interaction with and phosphorylation of Raf-1 in response to TNF alpha and ceramide analogs.
- In vitro kinase assays using natural ceramide and other lipid second messengers.
Main Results:
- Kinase suppressor of Ras (KSR) was identified as CAP kinase.
- Mouse KSR functions as a 100-kDa membrane-bound polypeptide that autophosphorylates.
- KSR overexpression leads to constitutive Raf-1 activation.
- TNF alpha and ceramide analogs significantly enhance KSR autophosphorylation, complex formation with Raf-1, and subsequent Raf-1 activation.
- KSR specifically phosphorylates Raf-1 at Thr269, the same site targeted by CAP kinase.
Conclusions:
- KSR functions as CAP kinase, playing a crucial role in the sphingomyelin pathway.
- KSR mediates TNF alpha-induced signaling by phosphorylating and activating Raf-1.
- These findings elucidate a key component of transmembrane signaling and inflammatory responses.
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