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SKK4, a novel activator of stress-activated protein kinase-1 (SAPK1/JNK)
S Lawler1, A Cuenda, M Goedert
1Department of Biochemistry, University of Dundee, UK. slawler@bad.dundee.ac.uk
Abstract:
A cDNA was cloned and expressed that encodes human stress-activated protein kinase kinase-4 (SKK4), a novel MAP kinase kinase family member whose mRNA is widely expressed in human tissues. SKK4 activated SAPK1/JNK in vitro, but not SAPK2a/p38, SAPK2b/p38beta, SAPK3/ERK6 or SAPK4. It appears to be the mammalian homologue of HEP, an activator of SAPK1/JNK in Drosophila. In human epithelial KB cells SKK4 and SKK1/MKK4 (another activator of SAPK1/JNK) were both activated by stressful stimuli, but only SKK4 was activated by proinflammatory cytokines. The identification of SKK4 explains why the major SAPK1/JNK activator detected in many mammalian cell extracts is chromatographically separable from SKK1/MKK4.
Insights
Researchers identified a new protein kinase, stress-activated protein kinase kinase-4 (SKK4), which activates SAPK1/JNK. This discovery explains differences in major SAPK1/JNK activators found in mammalian cells.
Area of Science:
- Molecular Biology
- Cell Signaling
Background:
- Stress-activated protein kinases (SAPKs) are crucial in cellular responses.
- The SAPK1/JNK pathway is activated by various cellular stresses.
- Understanding the regulators of SAPK1/JNK is vital for comprehending cellular signaling.
Purpose of the Study:
- To clone and characterize a novel MAP kinase kinase family member involved in stress signaling.
- To investigate the specific kinase activities of the newly identified protein.
- To elucidate the role of this new kinase in response to different stimuli.
Main Methods:
- cDNA cloning and expression of human stress-activated protein kinase kinase-4 (SKK4).
- In vitro kinase assays to determine substrate specificity (SAPK1/JNK, SAPK2a/p38, etc.).
- Activation studies in human epithelial KB cells using stressful stimuli and proinflammatory cytokines.
Main Results:
- Successfully cloned and expressed human SKK4, a novel MAP kinase kinase.
- SKK4 specifically activated SAPK1/JNK in vitro, but not other tested SAPKs.
- SKK4 and SKK1/MKK4 were activated by stress, but only SKK4 responded to proinflammatory cytokines.
- SKK4 is identified as the mammalian homologue of Drosophila HEP.
Conclusions:
- SKK4 is a novel and specific activator of the SAPK1/JNK pathway.
- SKK4 plays a distinct role in cellular responses, particularly to proinflammatory cytokines.
- The identification of SKK4 clarifies the presence of distinct SAPK1/JNK activators in mammalian cells.