Matrix Metalloproteinases 2 and 9 Mediate Epidermal Growth Factor Receptor Transactivation by Gonadotropin-releasing Hormone

Roelle, Susanne; Grosse, Robert; Aigner, Achim; Krell, Hans-Willi; Czubayko, Frank; Gudermann, Thomas

doi:10.1074/jbc.m304377200

Cited by 123 publications

(98 citation statements)

References 49 publications

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“…At this time there is no implication of the involvement of other G proteins in NT signaling in NCM460 cells. Because G proteins including G s (45), G i (28, 40), G q/11 (46,47), and G 13 (48) have been shown to mediate transactivation of the EGF receptor, further studies are needed to identify which G protein(s) mediates EGF receptor transactivation and to determine the signaling molecules involved in this NT response.…”

Section: Discussionmentioning

confidence: 99%

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Zhao¹,

Zhan²,

Koon³

et al. 2004

Journal of Biological Chemistry

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Expression of the neuropeptide neurotensin (NT) and its high affinity receptor (NTR1) is increased during the course of Clostridium difficile toxin A-induced acute colitis, and NTR1 antagonism attenuates the severity of toxin A-induced inflammation. We recently demonstrated in non-transformed human colonic epithelial NCM460 cells that NT treatment caused activation of a Ras-mediated MAP kinase pathway that significantly contributes to NT-induced interleukin-8 (IL-8) secretion. Here we used NCM460 cells, which normally express low levels of NTR1, and NCM460 cells stably transfected with NTR1 to identify the upstream signaling molecules involved in NT-NTR1-mediated MAP kinase activation. We found that inhibition of the epidermal growth factor receptor (EGFR) by either an EGFR neutralizing antibody or by its specific inhibitor AG1478 (0.2 M) blocked NT-induced MAP kinase activation. Moreover, NT stimulated tyrosine phosphorylation of the EGFR, and pretreatment with a broad spectrum metalloproteinase inhibitor batimastat reduced NT-induced MAP kinase activation. Using neutralizing antibodies against the EGFR ligands EGF, heparin-binding-EGF, transforming growth factor-␣ (TGF␣), or amphiregulin we have shown that only the anti-TGF␣ antibody significantly decreases NT-induced phosphorylation of EGFR and MAP kinases. Furthermore, inhibition of the EGF receptor by AG1478 significantly reduced NT-induced IL-8 promoter activity and IL-8 secretion. This is the first report demonstrating that NT binding to NTR1 transactivates the EGFR and that this response is linked to NT-mediated proinflammatory signaling. Our findings indicate that matrix metalloproteinase-mediated release of TGF␣ and subsequent EGFR transactivation triggers a NT-mediated MAP kinase pathway that leads to IL-8 gene expression in human colonic epithelial cells.Neurotensin (NT), 1 a 13-amino acid neuropeptide originally isolated by Carraway and Leeman (1) from bovine hypothalamus, is also localized in the gastrointestinal tract (2). In the small intestine NT is synthesized and secreted by specific mucosal endocrine cells in response to several different stimuli (3, 4). NT alters motility in the stomach, small bowel, and colon (5-7), stimulates secretion in the ileum (8), pancreas (9), and the biliary tract (10), and causes Cl Ϫ secretion from human colonic mucosa (11). NT also stimulates growth and regeneration of the intestinal mucosa (12, 13) and has been implicated in the pathophysiology of colon cancer (14, 15).Two G protein-coupled receptors (GPCRs) have been described for NT, a high affinity (NTR1) and a low affinity (NTR2) receptor (16). A third, non-G protein-coupled receptor has also been identified (17). Several studies underline the importance of NTR1 in several intestinal pathologic conditions. For example, administration of the specific NTR1 antagonist SR 48692 to rats inhibits colonic mucin and prostaglandin E2 secretion and mast cell activation in response to immobilization stress (18). NTR1 antagonism also reduces colonic secretion and infla...

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Section: Discussionmentioning

confidence: 99%

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Zhao¹,

Zhan²,

Koon³

et al. 2004

Journal of Biological Chemistry

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“…On the other hand, a recent study using the gonadotropinreleasing hormone receptor suggests that Src is involved in EGFR transactivation at a point distal to ligand shedding. Although treatment of cells with the Src family kinase inhibitor, PP2, did prevent gonadotropinreleasing hormone-stimulated EGFR1 transactivation, an inhibitor of gelatinase A and B (MMP 2 and 9) blocked activation of both EGFR1 and Src, placing Src in the pathway somewhere between ligand release and activation of the EGFR1 kinase (Roelle et al, 2003).…”

Section: Gpcr-mediated Transactivation Of Receptor Tyrosine Kinasesmentioning

confidence: 99%

Not so strange bedfellows: G-protein-coupled receptors and Src family kinases

2004

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Src family nonreceptor tyrosine kinases are an integral component of the signal transduction apparatus employed by growth factor receptor tyrosine kinases. As such, their role in cellular growth control and malignant transformation has been the subject of intensive investigation. In contrast, classical G-protein-coupled receptor (GPCR) signaling involves activation of second messenger-regulated serine/threonine kinases or ion channels, and is primarily involved in neurotransmission and the shortterm regulation of intermediary metabolism. Over the past decade, this strictly dichotomous model of transmembrane signaling has been challenged by the discovery that GPCRs also exert control over cellular growth, proliferation, and differentiation, and do so by stimulating tyrosine phosphorylation cascades. Several mechanisms, from the direct association of Src family kinases with GPCRs or receptor-associated proteins, to the transactivation of receptor tyrosine kinases and focal adhesion complexes by G-protein-mediated signals, permit GPCRs to activate Src family kinases. Conversely, Src activity plays a central role in controlling GPCR trafficking and effects on cell proliferation and cytoskeletal rearrangement. It is now clear that GPCRs and Src family kinases do not belong to separate, exclusive clubs. Rather, these strange bedfellows are intimately involved in multilayered forms of crosstalk that influence a host of cellular processes.

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“…Because GPCR-mediated EGFR transactivation has been shown to involve Src and to induce ERK activation (29,35,36), we then evaluated the effect of Src (PP2) and ERK (PD98059) inhibitors on S1P-stimulated MT1-MMP -dependent endothelial cell morphogenic differentiation and cell migration. Both processes were inhibited by PP2 and PD98059 ( Fig.…”

Section: Mt1-mmp -Dependent Morphogenic Differentiation and Endothelimentioning

confidence: 99%

“…Although the mechanisms involved in the EGFR transactivation remain incompletely understood, numerous studies suggest that the release of membraneassociated EGFR ligands by some members of the metalloprotease-disintegrin (ADAM; ref. 28) and MMP (29) families play an important role in this process, leading to tumor growth and invasion (26,(30)(31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation

Langlois

Nyalendo

Tomasso

et al. 2007

Molecular Cancer Research

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Proteolysis of extracellular matrix proteins by membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a pivotal role in tumor and endothelial cell migration. In addition to its proteolytic activity, several studies indicate that the proinvasive properties of MT1-MMP also involve its short cytoplasmic domain, but the specific mechanisms mediating this function have yet to be fully elucidated. Having previously shown that the serum factor sphingosine 1-phosphate stimulates MT1-MMP promigratory function through a process that involves its cytoplasmic domain, we now extend these findings to show that this cooperative interaction is permissive to cellular migration through MT1-MMP -dependent transactivation of the epidermal growth factor receptor (EGFR). In the presence of sphingosine 1-phosphate, MT1-MMP stimulates EGFR transactivation through a process that is dependent upon the cytoplasmic domain of the enzyme but not its catalytic activity. The MT1-MMP -induced EGFR transactivation also involves G i protein signaling and Src activities and leads to enhanced cellular migration through downstream extracellular signal-regulated kinase activation. The present study, thus, elucidates a novel role of MT1-MMP in signaling events mediating EGFR transactivation and provides the first evidence of a crucial role of this receptor activity in MT1-MMP promigratory function. Taken together, our results suggest that the inhibition of EGFR may represent a novel target to inhibit MT1-MMP -dependent processes associated with tumor cell invasion and angiogenesis. (Mol Cancer Res 2007;5(6):569 -83)

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Matrix Metalloproteinases 2 and 9 Mediate Epidermal Growth Factor Receptor Transactivation by Gonadotropin-releasing Hormone

Cited by 123 publications

References 49 publications

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells

Not so strange bedfellows: G-protein-coupled receptors and Src family kinases

Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation

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