Protein kinase D in vascular biology and angiogenesis

Evans, Ivor H.; Zachary, Ian

doi:10.1002/iub.456

Cited by 20 publications

(14 citation statements)

References 50 publications

(61 reference statements)

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“…These results also support the concept that terminally differentiated MVECs are developmentally plastic, and in the setting of specific environmental cues can be re-programmed 39–42 towards an arteriogenic phenotype that includes change in expression of surface proteins and secretion of factor(s) that support VSMC proliferation and migration. LPA is likely to be an important such cue as it is often generated in angiogenic microenvironments associated with inflammation, ischemia, platelet activation, cancer and obesity.…”

Section: Discussionsupporting

confidence: 81%

“…PKD-1-mediated signaling has been shown to regulate cardiovascular functions including myocardial responses to ischemia, angiogenesis, and arterial remodeling, 7, 20–24, 42, 45 and the transcription factor FoxO1 is well known to be involved in vascular development, postnatal angiogenesis, 32, 33 and regulation of EPHB2 expression 46 . Our study now links the PKD-1 signaling pathway initiated by specific LPA receptors to FoxO1 in MVECs and demonstrates a critical mechanistic role for nuclear accumulation of activated PKD-1 in recruiting a specific class II histone deacetylase, HDAC7, to the FoxO1 transcriptional regulatory complex.…”

Section: Discussionmentioning

confidence: 99%

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LPA/PKD-1-FoxO1 Signaling Axis Mediates Endothelial Cell CD36 Transcriptional Repression and Proangiogenic and Proarteriogenic Reprogramming

Ren

Best

Ramakrishnan

et al. 2016

ATVB

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Objective CD36 is a scavenger and antiangiogenic receptor that is important in atherothrombotic diseases, diabetes, cancer and obesity. Lysophosphatidic acid (LPA), a phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology domains by down-regulating endothelial CD36 transcription via protein kinase D1 (PKD-1) signaling. We aimed to understand mechanisms by which LPA-mediated angiogenic signaling is integrated to regulate CD36 transcription and endothelial cell function via a nuclear transcriptional complex. Approach and Results Microvascular endothelial cells (MVECs) expressing CD36 were used for studying angiogenic signaling and CD36 transcription. Gene transfection and transduction, RT-qPCR, avidin–biotin-conjugated DNA-binding assay, chromatin immunoprecipitation assay, co-immunoprecipitation, proximal ligation assay and immunofluorescence microscopy showed that LPA-mediated CD36 transcriptional repression involved PKD-1 signaling mediated formation of FoxO1-HDAC7 complex in the nucleus. Unexpectedly, turning off CD36 transcription initiated reprogramming MVECs to express ephrin B2 (EFNB2), a critical “molecular signature” involved in angiogenesis and arteriogenesis. Spheroid-based angiogenesis and in vivo Matrigel angiogenesis assays indicated that angiogenic branching morphogenesis and in vivo angiogenesis were dependent on PKD-1 signaling. A mouse tumor angiogenesis model revealed enhanced PKD-1 signaling and expression of EFNB2 and smooth muscle actin (SMA) in neovessels of Lewis Lung Carcinomas, along with low CD36 expression or CD36 deficiency. Conclusions LPA/PKD-1 signaling leads to nuclear accumulation of HDAC7, where it interacts with FoxO1 to suppress endothelial CD36 transcription and mediates silencing of antiangiogenic switch, resulting in proangiogenic and proarteriogenic reprogramming. Targeting this signaling cascade could be a novel approach for ischemic cardiovascular disease and cancer.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

LPA/PKD-1-FoxO1 Signaling Axis Mediates Endothelial Cell CD36 Transcriptional Repression and Proangiogenic and Proarteriogenic Reprogramming

Ren

Best

Ramakrishnan

et al. 2016

ATVB

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“…DAG recruits both PKDs to the cell membrane where they are activated primarily by novel PKC isoforms. Alternatively, activation of the VEGFR2 induces tyrosine phosphorylation of PKDs, tyrosine phosphorylated PKD mediates VEGF-induced proliferation [16], [17].…”

Section: Introductionmentioning

confidence: 99%

“…Targeting PKDs may not only impinge on tumor cell survival and proliferation directly, but also indirectly by an inhibitory effect on tumor vascularization. Several selective PKD inhibitors are currently under investigation [16], [19]. However, angiogenesis is a complex process that is regulated by multiple signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Different Regulation of Physiological and Tumor Angiogenesis in Zebrafish by Protein Kinase D1 (PKD1)

et al. 2013

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Protein kinase D isoenzymes (PKDs, Prkds) are serine threonine kinases that belong to the CAMK superfamily. PKD1 is expressed in endothelial cells and is a major mediator of biological responses downstream of the VEGFRs that are relevant for angiogenesis such as endothelial cell migration, proliferation and tubulogenesis in vitro. PKDs also play a critical role in tumor development and progression, including tumor angiogenesis. However, given the plethora of signaling modules that drive angiogenesis, the precise role of PKD1 in both physiological and tumor angiogenesis in vivo has not been worked out so far. This study aimed at dissecting the contribution of PKD1 to physiological blood vessel formation, PKD1 was found to be widely expressed during zebrafish development. As far as physiological angiogenesis was concerned, morpholino-based silencing of PKD1 expression moderately reduced the formation of the intersomitic vessels and the dorsal longitudinal anastomotic vessel in tg(fli1:EGFP) zebrafish. In addition, silencing of PKD1 resulted in reduced formation of the parachordal lymphangioblasts that serves as a precursor for the developing thoracic duct. Interestingly, tumor angiogenesis was completely abolished in PKD1 morphants using the zebrafish/tumor xenograft angiogenesis assay. Our data in zebrafish demonstrate that PKD1 contributes to the regulation of physiological angiogenesis and lymphangiogenesis during zebrafish development and is essential for tumor angiogenesis.

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“…However, PKD now constitutes a novel family of serine/threonine kinases and is classified as a subfamily of the calcium/calmodulin-dependent kinase superfamily. Recently, PKD has been shown to be dysregulated in several diseases, and it is regarded as a key regulator of diverse cellular functions such as cell growth, apoptosis, invasion and angiogenesis [37,38]. We have previously reported that VK2 suppressed the expression of MMPs, which are involved in the invasion and metastasis of cancer cells [15], in human HCC cell lines through the inhibition of NF-κB and/or the MAP kinase pathway [14].…”

Section: Discussionmentioning

confidence: 99%

The role of PKC isoforms in the inhibition of NF-κB activation by vitamin K2 in human hepatocellular carcinoma cells

Xia

Matsuhashi

Hamajima

et al. 2012

The Journal of Nutritional Biochemistry

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Protein kinase D in vascular biology and angiogenesis

Cited by 20 publications

References 50 publications

LPA/PKD-1-FoxO1 Signaling Axis Mediates Endothelial Cell CD36 Transcriptional Repression and Proangiogenic and Proarteriogenic Reprogramming

LPA/PKD-1-FoxO1 Signaling Axis Mediates Endothelial Cell CD36 Transcriptional Repression and Proangiogenic and Proarteriogenic Reprogramming

Different Regulation of Physiological and Tumor Angiogenesis in Zebrafish by Protein Kinase D1 (PKD1)

The role of PKC isoforms in the inhibition of NF-κB activation by vitamin K2 in human hepatocellular carcinoma cells

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