The Shedding of Membrane-anchored Heparin-binding Epidermal-like Growth Factor Is Regulated by the Raf/Mitogen-activated Protein Kinase Cascade and by Cell Adhesion and Spreading

Gechtman, Zeev; Alonso, José L.; Raab, Gerhard; Ingber, Donald E.; Klagsbrun, Michael

doi:10.1074/jbc.274.40.28828

Cited by 170 publications

(182 citation statements)

References 60 publications

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“…Shedding of L-selectin is observed shortly after adhesion to endothelial cells (40) and may be essential for PMN migration (48). Furthermore, shedding of L-selectin depends on TACE (ADAM17) (40) and is regulated among other things by the MAPK p38 (41,42). Given the fact that p38 MAPK phosphorylation is inducible by SCFA via GPR43, as shown in this study (Fig.…”

Section: Discussionmentioning

confidence: 82%

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Sina

Gavrilova²,

Förster³

et al. 2009

The Journal of Immunology

324

291

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Molecular danger signals attract neutrophilic granulocytes (polymorphonuclear leukocytes (PMNs)) to sites of infection. The G protein-coupled receptor (GPR) 43 recognizes propionate and butyrate and is abundantly expressed on PMNs. The functional role of GPR43 activation for in vivo orchestration of immune response is unclear. We examined dextrane sodium sulfate (DSS)-induced acute and chronic intestinal inflammatory response in wild-type and Gpr43-deficient mice. The severity of colonic inflammation was assessed by clinical signs, histological scoring, and cytokine production. Chemotaxis of wild-type and Gpr43-deficient PMNs was assessed through transwell cell chemotactic assay. A reduced invasion of PMNs and increased mortality due to septic complications were observed in acute DSS colitis. In chronic DSS colitis, Gpr43−/− animals showed diminished PMN intestinal migration, but protection against inflammatory tissue destruction. No significant difference in PMN migration and cytokine secretion was detected in a sterile inflammatory model. Ex vivo experiments show that GPR43-induced migration is dependent on activation of the protein kinase p38α, and that this signal acts in cooperation with the chemotactic cytokine keratinocyte chemoattractant. Interestingly, shedding of L-selectin in response to propionate and butyrate was compromised in Gpr43−/− mice. These results indicate a critical role for GPR43-mediated recruitment of PMNs in containing intestinal bacterial translocation, yet also emphasize the bipotential role of PMNs in mediating tissue destruction in chronic intestinal inflammation.

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Section: Discussionmentioning

confidence: 82%

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Sina

Gavrilova²,

Förster³

et al. 2009

The Journal of Immunology

324

291

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“…Interestingly, MDC9, which shares sequence similarity with TACE in its cytoplasmic domain, is phosphorylated by protein kinase C␦ (51). In one study this phosphorylation was shown to regulate the induction of HB-EGF shedding by PMA (51), whereas other findings indicate that PMA may activate HB-EGF shedding through the Erk MAP kinase signaling pathway instead (33,35). We now show that growth factor or PMA stimulation leads to enhanced phosphorylation of TACE through activation of the Erk MAP kinase signaling pathway.…”

mentioning

confidence: 95%

“…In contrast, little is as yet known about natural inducers and signaling pathways that activate ectodomain shedding under physiological conditions. Recent studies (32)(33)(34)(35)(36) have uncovered the roles of mitogen-activated protein (MAP) kinase signaling pathways in the activation of ectodomain shedding. Thus, growth factors and activated tyrosine kinase receptors rapidly induce ectodomain shedding of TGF-␣ and other transmembrane proteins through induction of the Erk MAP kinase signaling pathway without the need for new protein synthesis (32).…”

mentioning

confidence: 99%

“…Thus, growth factors and activated tyrosine kinase receptors rapidly induce ectodomain shedding of TGF-␣ and other transmembrane proteins through induction of the Erk MAP kinase signaling pathway without the need for new protein synthesis (32). PMA-induced ectodomain shedding of TGF-␣ or its family member heparin binding-epidermal growth factor-like growth factor (HB-EGF) and TNF-␣ is also mediated through activation of the Erk signaling pathway (32,33,35). In addition, activation of the p38 MAP kinase pathway, often a result of inflammatory mediators or physiological stress, also leads to ectodomain shedding (32,37).…”

mentioning

confidence: 99%

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Characterization of Growth Factor-induced Serine Phosphorylation of Tumor Necrosis Factor-α Converting Enzyme and of an Alternatively Translated Polypeptide

Fan

Turck

Derynck

2003

Journal of Biological Chemistry

107

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Tumor necrosis factor-␣ converting enzyme (TACE) is a prototype member of the adamalysin family of transmembrane metalloproteases that effects ectodomain cleavage and release of many transmembrane proteins, including transforming growth factor-␣. Growth factors that act through tyrosine kinase receptors, as well as other stimuli, induce shedding through activation of the Erk mitogen-activated protein (MAP) kinase pathway without the need of new protein synthesis. How MAP kinase regulates shedding by TACE is not known. We now report that the cytoplasmic domain of TACE is phosphorylated in response to growth factor stimulation. We also identified a naturally expressed smaller polypeptide corresponding to most of the cytoplasmic domain of TACE. This protein, which we named SPRACT, is derived through alternative translation of the TACE-coding sequence and is, similarly to TACE, phosphorylated in response to growth factor and phorbol 12-myristate 13-acetate stimulation. Phosphoamino acid analysis revealed that growth factor-induced phosphorylation of TACE occurs only on serine and not on threonine or tyrosine. Tryptic mapping experiments coupled with site-directed mutagenesis identified Ser 819 as the major target of growth factor-induced phosphorylation, whereas Ser 791 undergoes dephosphorylation in response to growth factor stimulation. The phosphorylation of Ser 819 , but not the dephosphorylation of Ser 791 , depends on activation of the Erk MAP kinase pathway. Increased SPRACT expression or mutation of the TACE cytoplasmic domain to inactivate growth factor-induced phosphorylation did not detectably affect growth factor-induced shedding of transmembrane transforming growth factor-␣ by TACE. The roles of SPRACT and the cytoplasmic phosphorylation of TACE remain to be defined.

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“…The immune complexes were incubated with 40 l of protein G-Sepharose (50% vol͞vol slurry) for 1.5 hr at 4°C, washed four times with lysis buffer, and boiled in 2ϫ Laemmli's sample buffer. Proteins were resolved on 7% SDS͞PAGE and analyzed by Western blot by using monoclonal antiphosphotyrosine antibodies (16).…”

Section: Binding Of 125 I-vegf165 To Snrp1 and To Cells Binding In Smentioning

confidence: 99%

Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor:In vivoexpression and antitumor activity

Gagnon

Bielenberg²,

Gechtman³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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286

314

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Neuropilin-1 (NRP1) is a 130-kDa transmembrane receptor for semaphorins, mediators of neuronal guidance, and for vascular endothelial growth factor 165 (VEGF165), an angiogenesis factor. A 2.2-kb truncated NRP1 cDNA was cloned that encodes a 644-aa soluble NRP1 (sNRP1) isoform containing just the a͞CUB and b͞coagulation factor homology extracellular domains of NRP1. sNRP1 is secreted by cells as a 90-kDa protein that binds VEGF165, but not VEGF121. It inhibits 125 I-VEGF165 binding to endothelial and tumor cells and VEGF165-induced tyrosine phosphorylation of KDR in endothelial cells. The 3 end of sNRP1 cDNA contains a unique, 28-bp intron-derived sequence that is absent in full-length NRP1 cDNA. Using a probe corresponding to this unique sequence, sNRP1 mRNA could be detected by in situ hybridization differentially from full-length NRP1 mRNA, for example, in cells of liver, kidney, skin, and breast. Analysis of blood vessels in situ showed that NRP1, but not sNRP1, was expressed. sNRP1 was functional in vivo. Unlike control tumors, tumors of rat prostate carcinoma cells expressing recombinant sNRP1 were characterized by extensive hemorrhage, damaged vessels, and apoptotic tumor cells. These results demonstrate the existence of a naturally occurring, soluble NRP1 that is expressed differently from intact NRP1 and that appears to be a VEGF165 antagonist.tumor angiogenesis ͉ prostate carcinoma cells ͉ apoptosis ͉ receptor N europilin-1 (NRP1) is a transmembrane glycoprotein, first described in the developing nervous system, that is expressed on axons of dorsal root ganglia, sensory, and motor neurons (1). NRP1 is a receptor for several members of the semaphorin͞collapsin family, negative mediators of neuronal guidance (2, 3). NRP1 was shown by us also to be an isoformspecific receptor for vascular endothelial growth factor (VEGF) that binds VEGF 165 but not VEGF 121 to the surface of endothelial cells (EC) and tumor cells (4). VEGF 165 is an EC mitogen in vitro and angiogenesis factor in vivo whose activities are mediated by the VEGF tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1͞KDR (VEGFR2) (reviewed in refs. 5-8). Expression of NRP1 in EC enhances the binding of VEGF 165 to KDR and VEGF 165 -induced EC chemotaxis (4). Thus, it appears that in EC, NRP1 acts as a coreceptor that enhances KDR activity. The involvement of NRP1 in angiogenesis is supported by the observation that overexpression of NRP1 in transgenic mice results in excess capillary and blood vessel formation (9). The consequences of VEGF 165 binding to tumor cell NRP1 have not yet been determined. A role for semaphorin interactions with NRP1 in angiogenesis has been suggested by the ability of semaphorin III͞collapsin-1, an inhibitor of axonal motility, to inhibit the migration of EC in a NRP1-dependent manner (10). Inhibition of EC motility is associated with the depolymerization of F-actin and retraction of lamellipodia in a manner similar to growth cone collapse.In our initial Northern blot analysis of NRP1 gene expression, we noticed that b...

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The Shedding of Membrane-anchored Heparin-binding Epidermal-like Growth Factor Is Regulated by the Raf/Mitogen-activated Protein Kinase Cascade and by Cell Adhesion and Spreading

Cited by 170 publications

References 60 publications

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Characterization of Growth Factor-induced Serine Phosphorylation of Tumor Necrosis Factor-α Converting Enzyme and of an Alternatively Translated Polypeptide

Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor:In vivoexpression and antitumor activity

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