VEGF stimulates PKD‐mediated CREB‐dependent orphan nuclear receptor Nurr1 expression: Role in VEGF‐induced angiogenesis

Zhao, Dan; Desai, Sachin N.; Zeng, Hui

doi:10.1002/ijc.25600

Cited by 44 publications

(42 citation statements)

References 42 publications

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“…Indeed, gremlin causes CREB activation, nuclear translocation, and DNA binding in ECs through a productive gremlin-VEGFR2 interaction. PI-3K and PKC mediate CREB activation after VEGFR2 engagement by 17 Our observations demonstrate a nonredundant role of VEGFR2-mediated mitogen activated protein kinase and Src signaling in CREB activation by gremlin, whereas no effect was exerted by the PI-3K inhibitors LY294002 and Wortmannin or the PKC inhibitor GF109203X (data not shown). Together with the different kinetics of CREB activation by the 2 factors, these data reveal the previously unrecognized capacity of gremlin to trigger VEGFR2-dependent intracellular events distinct from those elicited by VEGF-A.…”

mentioning

confidence: 68%

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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Objective-Angiogenesis and inflammation are closely related processes. Gremlin is a novel noncanonical vascular endothelial growth factor receptor-2 (VEGFR2) ligand that induces a proangiogenic response in endothelial cells (ECs).Here, we investigated the role of the cyclic adenosine monophosphate-response element (CRE)-binding protein (CREB) in mediating the proinflammatory and proangiogenic responses of ECs to gremlin. Approach and Results-Gremlin induces a proinflammatory response in ECs, leading to reactive oxygen species and cyclic adenosine monophosphate production and the upregulation of proinflammatory molecules involved in leukocyte extravasation, including chemokine (C-C motif) ligand-2 (Ccl2) and Ccl7, chemokine (C-X-C motif) ligand-1 (Cxcl1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). Accordingly, gremlin induces the VEGFR2-dependent phosphorylation, nuclear translocation, and transactivating activity of CREB in ECs. CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to monocyte/macrophage adhesion to ECs and their extravasation. All these effects are inhibited by EC transfection with a dominant-negative CREB mutant or with a CREB-binding protein-CREB interaction inhibitor that competes for CREB/CRE binding. Also, both recombinant gremlin and gremlin-expressing tumor cells induce proinflammatory/proangiogenic responses in vivo that are suppressed by the anti-inflammatory drug hydrocortisone. Corsini et al CREB in Gremlin Activity 137diseases 24 and cancer. [25][26][27] Gremlin acts as a bone morphogenic protein (BMP) antagonist by binding BMP2, BMP4, and BMP7. 28 Also, gremlin stimulates EC intracellular signaling and motility in a BMP-independent manner, leading to a potent angiogenic response in vivo. 27,29 This is because of the capacity of gremlin to bind and activate VEGF receptor-2 (VEGFR2), the main transducer of VEGF-mediated angiogenic signals. 30,31 Also, gremlin interacts with heparan-sulfate proteoglycans that act as functional gremlin coreceptors in ECs, affecting its productive interaction with VEGFR2.32 However, at variance with heparin-binding VEGFs, gremlin does not interact with the coreceptor neuropilin-1. 32 Thus, gremlin is a novel proangiogenic VEGFR2 agonist distinct from canonical VEGFs.Here, we demonstrate that gremlin induces a proinflammatory response in ECs by inducing the expression of various chemokines and cell adhesion molecules, causing a VEGFR2-mediated activation of CREB. In turn, CREB activation mediates the early phases of the angiogenic response to gremlin, including stimulation of EC motility and permeability, and leads to leukocyte-adhesion to ECs and their extravasation. In keeping with these observations, gremlin and gremlin-expressing tumor cells induce a proinflammatory or proangiogenic response in vivo that is suppressed by the anti-inflammatory drug hydrocortisone. These data point to a nonredundant role of CRE...

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confidence: 68%

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Corsini

Moroni

Ravelli

et al. 2014

ATVB

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“…NR4A receptors are downstream targets of VEGF, promoting proliferation of endothelial cells in vitro and in vivo (25,28). Transcription of NR4A receptors is increased by VEGF, hypoxia, and CREB activation in vascular endothelial cells (25).…”

Section: Metabolism and Angiogenesismentioning

confidence: 99%

“…Transcription of NR4A receptors is increased by VEGF, hypoxia, and CREB activation in vascular endothelial cells (25). In vivo, the transcriptional activity of NR4A1 and NR4A2 is involved in VEGF-mediated angiogenesis (28,29).…”

Section: Metabolism and Angiogenesismentioning

confidence: 99%

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Mohan

Aherne

Rogers

et al. 2012

Clinical Cancer Research

158

142

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Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kB, phosphoinositide 3-kinase/AKT, c-jun-NH 2 -kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-¡). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation.

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“…PKD directly phosphorylates the transcription factor CREB to allow recruitment of coactivators, including CREB binding protein (CBP)/p300, and augment CREB-mediated gene expression (26). In a recent study, CREB dependent transcription of the immediate-early gene, Nurr1, was found to be important for in vivo angiogenesis in a mouse model using matrigel plugs (27). Furthermore, PKD can also phosphorylate several members of the Class IIa histone deacetylase (HDAC) family, notably HDAC5 and HDAC7 (10,28,29).…”

Section: Pkd Function In Endothelial Cellsmentioning

confidence: 99%

Protein kinase D in vascular biology and angiogenesis

Evans

Zachary

2011

IUBMB Life

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SummaryThe 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.

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VEGF stimulates PKD‐mediated CREB‐dependent orphan nuclear receptor Nurr1 expression: Role in VEGF‐induced angiogenesis

Cited by 44 publications

References 42 publications

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Cyclic Adenosine Monophosphate-Response Element–Binding Protein Mediates the Proangiogenic or Proinflammatory Activity of Gremlin

Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer

Protein kinase D in vascular biology and angiogenesis

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