Cell-specific cyclic AMP-mediated induction of the PDGF receptor.

Weinmaster, Gerry; Lemke, Greg

doi:10.1002/j.1460-2075.1990.tb08189.x

Cited by 124 publications

(105 citation statements)

References 45 publications

(58 reference statements)

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“…This specific behavior was reversible, in that removal ofthe cells from the 3D culture environment and placement in a 2D culture environment elicited reexpression of a smooth muscle actin. The cells retain their expression of Factor VIII-related antigen (18,41) (46,48); both receptor subunits are upregulated by PDGF BB (49) and the (3 receptor expression is elevated by increased cAMP (50). The present report demonstrates PDGF receptor downregulation and growth arrest induced by the phenotypic modulation of microvascular endothelial cells in a three-dimensional environment.…”

Section: Resultsmentioning

confidence: 64%

Modulation of platelet-derived growth factor receptor expression in microvascular endothelial cells during in vitro angiogenesis.

Marx¹,

Perlmutter²,

Madri³

1994

J. Clin. Invest.

140

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Microvascular endothelial cells in vivo exhibit a plastic phenotype, forming a nonproliferative, differentiated capillary network, while retaining their ability to respond to injury by proliferation, migration and neovascularization. The presence of PDGF receptors and PDGF responsiveness in microvascular endothelial cells and the significance of PDGF isoforms in the control of endothelial cell growth and differentiation remain controversial. Since culture of microvascular endothelial cells in a three-dimensional (3D) system induced cell differentiation and angiogenesis and inhibited proliferation, the present study investigates the role of different extracellular matrix environments in inducing different microvascular endothelial cell phenotypes on microvascular endothelial cell PDGF receptor expression and PDGF responsiveness. In conventional two-dimensional (2D) culture, microvascular endothelial cells expressed both PDGF receptor a and fi chains. Suramin treatment demonstrated continuous downregulation of the a receptor surface expression. PDGF BB and, to a lesser extent, PDGF AB were mitogenic in 2D-culture, PDGF AA failed to induce any proliferative response despite inducing receptor autophosphorylation. During in vitro angiogenesis induced by 3D-culture, both PDGF receptors were rapidly downregulated. Assessment of cell proliferation showed quiescent cells and PDGF unresponsiveness. We conclude that the induction of a differentiated phenotype during in vitro angiogenesis (tube formation) driven in part by the spatial organization of the surrounding matrix is associated with a downregulation of PDGF receptors. Identification of the molecular cell-matrix interactions involved in this receptor regulation may allow for targeted manipulation of cell growth in vivo and lead to novel therapeutic applications for PDGF. (J. Clin. Invest. 1994. 93:131-139.)

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Section: Resultsmentioning

confidence: 64%

Modulation of platelet-derived growth factor receptor expression in microvascular endothelial cells during in vitro angiogenesis.

Marx¹,

Perlmutter²,

Madri³

1994

J. Clin. Invest.

140

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“…This mechanism is distinct from that demonstrated previously for PDGF. Forskolin has been reported to be required for expression of PDGF receptors by Schwann cells (34).…”

Section: Discussionmentioning

confidence: 99%

“…This is in contrast to most cell types, whose proliferation is inhibited by cAMP (3,13,31). cAMP has been reported to be required for expression of PDGF and insulin-like growth factor receptors in Schwann cells (34).…”

mentioning

confidence: 89%

Synergistic Regulation of Schwann Cell Proliferation by Heregulin and Forskolin

Rahmatullah

Schroering

Rothblum

et al. 1998

Molecular and Cellular Biology

103

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A peptide corresponding to the epidermal growth factor homology domain of ␤-heregulin stimulated autophosphorylation of the heregulin receptors erbB2 and erbB3 in Schwann cells and activation of the mitogen-activated protein (MAP) kinases ERK1 and ERK2. Heregulin-dependent activation of PAK65, a component of the stress-activated signaling pathway, ribosomal S6 kinase, and a cyclic AMP (cAMP) response element binding protein (CREB) kinase, identified as p95 RSK2, was also observed. Receptor phosphorylation and activation of these kinases in response to heregulin occurred in the absence of forskolin stimulation and were not augmented in cells treated with forskolin, a direct activator of adenylyl cyclase. Schwann cell proliferation in response to heregulin was observed only when the cells were also exposed to an agent that elevates cAMP levels. In the absence of heregulin, elevation of cAMP levels failed to stimulate Schwann cell proliferation. Forskolin significantly enhanced heregulin-stimulated expression of cyclin D and phosphorylation of the retinoblastoma gene product. In cells treated with both heregulin and forskolin there was a sustained accumulation of phospho-CREB, which was not observed in cells treated with either agent alone. Heregulin and forskolin synergistically activated transcription of a cyclin D promoter construct. These results demonstrate that heregulin-stimulated activation of MAP kinase is not sufficient to induce maximal Schwann cell proliferation. Expression of critical cell cycle regulatory proteins and cell division require activation of both heregulin and cAMP-dependent processes.Myelination of axons by Schwann cells is critical for the proper functioning of the peripheral nervous system. The correct ratio of Schwann cells to axons is achieved during development through a combination of Schwann cell proliferation (26) and programmed cell death (29). Studies with primary cultures of Schwann cells and embryonic sensory neurons have shown that molecular signals that stimulate Schwann cell proliferation are associated with axonal membranes (24,27,35).Several lines of evidence suggest that the axonal Schwann cell mitogen is a member of the heregulin family of growth factors (5,9,17,21). A common structural feature of heregulins is a cysteine-rich domain of approximately 50 amino acids that is homologous to the active domain of epidermal growth factor (EGF) (18). Heregulins stimulate cell proliferation by binding to and activating transmembrane receptor tyrosine kinases with homology to the EGF receptor, called erbB2, erbB3, and erbB4 (10, 25). A synthetic peptide corresponding to the heregulin EGF homology domain is sufficient to mediate binding to erbB receptors (2). Ligand-dependent activation of erbB receptors leads to activation of the mitogen-activated protein (MAP) kinase pathway, which is critical for cell division in many cell types (22).Schwann cell proliferation can also be stimulated by other polypeptide growth factors (6), including basic fibroblast growth factor and platelet-d...

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“…Mouse primary Schwann cell culture Mouse SC cultures were established from neonatal sciatic nerves as described (Weinmaster and Lemke 1990). Sciatic nerves dissected from P2 mice were enzymatically treated with 0.5 mg/mL collagenase type I (Invitrogen) and 2.5 mg/mL dispase II (Roche), followed by mechanical dissociation through 18, 21, and 23 gauge needles.…”

Section: Cell Culturementioning

confidence: 99%

Phosphatidic acid mediates demyelination in Lpin1 mutant mice

Nadra¹,

Charles²,

Médard³

et al. 2008

Genes Dev.

130

149

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Lipids play crucial roles in many aspects of glial cell biology, affecting processes ranging from myelin membrane biosynthesis to axo-glial interactions. In order to study the role of lipid metabolism in myelinating glial cells, we specifically deleted in Schwann cells the Lpin1 gene, which encodes the Mg 2+ -dependent phosphatidate phosphatase (PAP1) enzyme necessary for normal triacylglycerol biosynthesis. The affected animals developed pronounced peripheral neuropathy characterized by myelin degradation, Schwann cell dedifferentiation and proliferation, and a reduction in nerve conduction velocity. The observed demyelination is mediated by endoneurial accumulation of the substrate of the PAP1 enzyme, phosphatidic acid (PA). In addition, we show that PA is a potent activator of the MEK-Erk pathway in Schwann cells, and that this activation is required for PA-induced demyelination. Our results therefore reveal a surprising role for PA in Schwann cell fate determination and provide evidence of a direct link between diseases affecting lipid metabolism and abnormal Schwann cell function.[Keywords: Schwann cells; myelin; peripheral neuropathy; lipid metabolism; phosphatidic acid] Supplemental material is available at http://www.genesdev.org.

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Cell-specific cyclic AMP-mediated induction of the PDGF receptor.

Cited by 124 publications

References 45 publications

Modulation of platelet-derived growth factor receptor expression in microvascular endothelial cells during in vitro angiogenesis.

Modulation of platelet-derived growth factor receptor expression in microvascular endothelial cells during in vitro angiogenesis.

Synergistic Regulation of Schwann Cell Proliferation by Heregulin and Forskolin

Phosphatidic acid mediates demyelination in Lpin1 mutant mice

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