E-Cadherin Facilitates Protein Kinase D1 Activation and Subcellular Localization.

Abstract

Protein kinase D 1 (PKD1) is a serine/threonine kinase implicated in the regulation of diverse cellular functions including cell growth, differentiation, adhesion and motility. The current model for PKD1 activation involves diacylglycerol (DAG) binding to the C1 domain of PKD1 which results in the translocation of PKD1 to subcellular membranes where PKD1 is phosphorylated and activated by protein kinase C (PKC). In this study, we have identified a novel regulation of PKD1 activation. The epithelial cell membrane protein E-cadherin physically binds to PKD1 which leads to a subcellular redistribution of PKD1. Furthermore, artificial targeting of PKD1 to the membrane leads to PKD1 activation in a PKC-independent manner, indicating that membrane attachment is sufficient enough to activate PKD1. The presence of E-cadherin dynamically regulates PKD1 activation by Bryostatin 1, a potent activator of PKD1, and its substrate phosphorylation specificity, implying a loss of E-cadherin during cancer metastasis could cause the re-distribution PKD1 and re-wiring of PKD1 signaling for distinct functions. The knocking down of PKD1 in lung epithelial cell line A549 results in an epithelial to mesenchymal transition with changes in biomarker expression, cell migration and drug resistance. These results extend our previous understanding of PKD1 regulation and E-cadherin signaling functions and may help to explain the diversified functions of PKD1 in various cells. J. Cell. Physiol. 231: 2741-2748, 2016. © 2016 Wiley Periodicals, Inc.

• Authors: Zhuo Li, Chuanyou Zhang, Li Chen, Guosheng Li, Ling Qu, K C Balaji, Cheng Du
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 231 Issue 12 Pg. 2741-8 (12 2016) ISSN: 1097-4652 [Electronic] United States
• PMID: 26991955 (Publication Type: Journal Article)
• Copyright: © 2016 Wiley Periodicals, Inc.

Chemical References

• Antigens, CD
• CDH1 protein, human
• Cadherins
• protein kinase D
• Protein Kinase C

Topics

• Antigens, CD
• Cadherins (metabolism)
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Movement
• Drug Resistance, Neoplasm
• Enzyme Activation
• Epithelial-Mesenchymal Transition
• Gene Knockdown Techniques
• Humans
• Kinetics
• Phosphorylation
• Protein Binding
• Protein Kinase C (metabolism)
• Protein Transport
• Subcellular Fractions (enzymology)
• Substrate Specificity