Abstract
The Protein Kinase D (PKD) isoforms PKD1, PKD2, and PKD3 are effectors of the novel Protein Kinase Cs (nPKCs) and diacylglycerol (DAG). PKDs impact diverse biological processes like protein transport, cell migration, proliferation, epithelial to mesenchymal transition (EMT) and apoptosis. PKDs however, have distinct effects on these functions. While PKD1 blocks EMT and cell migration, PKD2 and PKD3 tend to drive both processes. Given the importance of EMT and cell migration to the initiation and progression of various malignancies, abnormal expression of PKDs has been reported in multiple types of cancers, including breast, pancreatic and prostate cancer. In this review, we discuss how EMT and cell migration are regulated by PKD isoforms and the significance of this regulation in the context of cancer development.
Highlights
Protein Kinase D family members are serine/threonine kinases that function downstream of the novel Protein Kinase Cs and diacylglycerol
There is a growing body of evidence which shows that Protein Kinase D (PKD) family members are key regulators of epithelial to mesenchymal transition (EMT) and cell migration
It is well-established that PKD1 through the phosphorylation of Snail and other regulatory molecules contributes to the maintenance of the epithelial phenotype and blocks cell migration
Summary
Protein Kinase D family members are serine/threonine kinases that function downstream of the novel Protein Kinase Cs and diacylglycerol. PKD activation has been shown to occur in response to oxidative stress [10,11,12], binding of G beta-gamma (Gβγ) proteins to the PKD family PH domain at the Golgi [13], as well as caspase 3-mediated proteolytic cleavage [14]. Even though aforementioned demonstrate that PKD isoforms, dependent on the signaling pathway, family members have similar modular structures, they doPKD exhibit some structural variability. PKD1 is highly-expressed in ductal epithelial cells of the normal breast while its expression is downregulated in highly‐invasive breast cancers [29,49]. We discuss how PKD isoforms contribute to EMT and cell migration, two biological processes relevant for tumor development and progression.
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