Protein kinase D in vascular biology and angiogenesis

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Abstract

The Protein Kinase D (PKD) family comprises diacylglycerol stimulated serine/threonine protein kinases that participate in many key signaling pathways in a diverse range of cells. Recent studies show that PKD isoforms 1 and 2 play critical roles in vascular biology and angiogenesis and there has been considerable progress in determining some of the key angiogenic signaling pathways mediated by PKD in endothelial cells. Less is currently known regarding the specific roles of PKD isoforms in endothelial cells and the role of PKD in smooth muscle cells. PKD is also emerging as a potentially important mediator of tumor growth and tumor angiogenesis and there is growing interest in PKD as a novel therapeutic target in cancer. Copyright © 2011 Wiley Periodicals, Inc.

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The protein kinase complement of the human genome.

G. Manning (2002)

We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.

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PKD at the crossroads of DAG and PKC signaling.

Andrew Wang (2006)

Diacylglycerol (DAG) and its primary target protein kinase C (PKC) regulate many important cellular responses, yet the molecular mechanisms that control the specificity of DAG and PKC signaling are not fully understood. As such, targeting the PKC pathway for therapeutic purposes has been challenging. Protein kinase D (PKD), a novel DAG receptor, has been the subject of intense investigation in recent years. DAG regulates the intracellular localization of PKD and also activates PKD through PKC by phosphorylation. The PKC-PKD signaling cascade is crucial to PKD function in cells. Important discoveries have been made regarding the roles of PKD in cell growth, gene expression, survival, motility, protein trafficking and lymphocyte biology. This kinase is implicated in pathological processes such as cardiac hypertrophy, tumor cell proliferation and metastasis. Thus, PKD represents a novel therapeutic target for the DAG-PKC signaling network.

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Integrins: the keys to unlocking angiogenesis.

Gabriela D’Amico, Louise E. Reynolds, K Hodivala-Dilke … (2008)

Angiogenesis, the formation of new blood vessels from preexisting vasculature, contributes to the pathogenesis of many disorders, including ischemic diseases and cancer. Integrins are cell adhesion molecules that are expressed on the surface of endothelial cells and pericytes, making them potential targets for antiangiogenic therapy. Here we review the contribution of endothelial and mural cell integrins to angiogenesis and highlight their potential as antiangiogenesis targets.