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GTP-dependent secretion from neutrophils is regulated by Cdk5
Jesusa L Rosales1, Joel D Ernst, Janice Hallows
1Department of Cell Biology and Anatomy, Cancer Biology and Neuroscience Research Groups, The University of Calgary, Calgary, Alberta T2N 4N1, Canada. rosales@ucalgary.ca
The Journal of Biological Chemistry
|October 20, 2004
Summary
Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are present in neutrophils and regulate GTP-induced secretion. Cdk5-p35 activity is crucial for maximal lactoferrin release and surface marker expression during neutrophil degranulation.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Neutrophil secretion is calcium-independent and GTP-regulated.
- Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are known regulators of neuronal secretion.
- The role of Cdk5-p35 in neutrophil function is largely unknown.
Purpose of the Study:
- To investigate the presence and function of Cdk5-p35 in neutrophils.
- To elucidate the role of Cdk5-p35 in GTP-regulated neutrophil secretion.
Main Methods:
- Detection and localization of Cdk5-p35 in human neutrophils.
- Assessment of Cdk5-p35 activity in secretory granules upon GTP stimulation.
- Inhibition of Cdk5 activity using roscovitine and assessment of its effects on secretion.
- Analysis of neutrophil secretion markers (lactoferrin, CD63, CD66b) in wild-type and p35 knockout mice.
Main Results:
- Active Cdk5-p35 complex is present in human neutrophils, localized in secretory granules.
- GTP stimulation increases Cdk5-p35 level and activity in granules, correlating with lactoferrin secretion.
- Cdk5 inhibition by roscovitine reduces GTP-induced lactoferrin secretion and surface marker expression.
- Neutrophils lacking p35 or treated with roscovitine show impaired GTP-induced secretion.
Conclusions:
- Cdk5-p35 is a key component of the GTP-regulated secretory apparatus in neutrophils.
- Cdk5-p35 is required for maximal GTP-induced lactoferrin secretion and surface marker mobilization.
- Neutrophil granule proteins are specific substrates of Cdk5, supporting its role in secretion.