c-Src Is Activated by the Epidermal Growth Factor Receptor in a Pathway That Mediates JNK and ERK Activation by Gonadotropin-releasing Hormone in COS7 Cells

Kraus, Sarah; Benard, Outhiriaradjou; Naor, Zvi; Seger, Rony

doi:10.1074/jbc.m303886200

Cited by 69 publications

(27 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The results obtained by ribozyme transfection were in perfect agreement with the conclusions drawn from pharmacological inhibition of MMPs. In contrast to our findings, the blockage of EGFR tyrosine kinase activity by the selective tyrphostin AG1478 has been reported not to affect ERK activation via the GnRHR in the same cell line calling into question the relevance of EGFR transactivation for GnRH signaling to ERKs (42), whereas the involvement of the EGFR and Src kinases in the signal transmission from the GnRHR to MAPKs has recently been emphasized by the same researchers (43). Furthermore, GnRH-induced signaling to ERKs in hypothalamic neurons critically depends on EGFR transactivation (44).…”

Section: The Induction Of C-fos and C-jun Depends On Gelatinase Activcontrasting

confidence: 55%

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

Roelle

Grosse

Aigner

et al. 2003

Journal of Biological Chemistry

122

View full text Add to dashboard Cite

Section: The Induction Of C-fos and C-jun Depends On Gelatinase Activcontrasting

confidence: 55%

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

Roelle

Grosse

Aigner

et al. 2003

Journal of Biological Chemistry

122

View full text Add to dashboard Cite

“…These include several GPCR agonists, cytokines, adhesion receptor ligands (integrin), membrane depolarizing agents (KCl), steroid hormones (estrogen), and environmental stresses (radiation, heat shock, and trauma) (7-10, 35, 36). Not all of these stimuli cause activation of metalloprotease(s) and production of HB-EGF to activate the EGF-R (29,37,38). However, the present observations have defined the intermediary action of metalloprotease-dependent shedding of HB-EGF in transactivation of the EGF-R by GnRH in GT1-7 neuronal cells.…”

Section: Fig 8 Pkc Acts Upstream Of Metalloprotease Inductionmentioning

confidence: 54%

“…Ectodomain shedding is induced by various GPCRs (6,42), GTP␥S (43), PMA (6,44), Ca 2ϩ (9,27), Src (35,40), and derivatives of arachidonic acid metabolism such as prostaglandins and leukotrienes (42) and ROS (43)(44)(45). Although substantial evidence supports the role of metalloprotease-dependent shedding of HB-EGF in transducing signals from GPCRs to the EGF-R (6,14), some studies have excluded their involvement in this process (29,37,38). Likewise, we did not observe GnRH-mediated induction of metalloproteases and activation of EGF-R in HEK293 cells expressing the GnRH receptor (Fig.…”

Section: ϩ2mentioning

confidence: 99%

Neuropeptide-induced Transactivation of a Neuronal Epidermal Growth Factor Receptor Is Mediated by Metalloprotease-dependent Formation of Heparin-binding Epidermal Growth Factor

Shah

Farshori

Catt

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Numerous external stimuli, including G protein-coupled receptor agonists, cytokines, growth factors, and steroids activate mitogen-activated protein kinases (MAPKs) through phosphorylation of the epidermal growth factor receptor (EGF-R). In immortalized hypothalamic neurons (GT1-7 cells), agonist binding to the gonadotropin-releasing hormone receptor (GnRH-R) causes phosphorylation of MAPKs that is mediated by protein kinase C (PKC)-dependent transactivation of the EGF-R. An analysis of the mechanisms involved in this process showed that GnRH stimulation of GT1-7 cells causes release/shedding of the soluble ligand, heparin binding epidermal growth factor (HB-EGF), as a consequence of metalloprotease activation. GnRH-induced phosphorylation of the EGF-R and, subsequently, of Shc, ERK1/2, and its dependent protein, p90 RSK-1 (p90 ribosomal S6 kinase 1 or RSK-1), was abolished by metalloprotease inhibition. Similarly, blockade of the effect of HB-EGF with the selective inhibitor CRM197 or a neutralizing antibody attenuated signals generated by GnRH and phorbol 12-myristate 13-acetate, but not those stimulated by EGF. In contrast, phosphorylation of the EGF-R, Shc, and ERK1/2 by EGF and HB-EGF was independent of PKC and metalloprotease activity. The signaling characteristics of HB-EGF closely resembled those of GnRH and EGF in terms of the phosphorylation of EGF-R, Shc, ERK1/2, and RSK-1 as well as the nuclear translocation of RSK-1. However, neither the selective Src kinase inhibitor PP2 nor the overexpression of negative regulatory Src kinase and dominant negative Pyk2 had any effect on HB-EGF-induced responses. In contrast to GT1-7 cells, human embryonic kidney 293 cells expressing the GnRH-R did not exhibit metalloprotease induction and EGF-R transactivation during GnRH stimulation. These data indicate that the GnRH-induced transactivation of the EGF-R and the subsequent ERK1/2 phosphorylation result from ectodomain shedding of HB-EGF through PKC-dependent activation of metalloprotease(s) in neuronal GT1-7 cells.

show abstract

“…Indeed, Adayev et al (38) have demonstrated the importance of PLC␤ in the 5-HT 1A receptor-mediated ERK activation via G␣ q , and others have also confirmed the abilities of PKC and CaMKII to regulate ERK, requiring the Raf-1 kinase (39,40). In addition, the regulatory role of c-Src for modulating the activities of Ras (31) and ERK (41) has been demonstrated. Indeed, recent reports suggested a role of ␤-arrestin2 in scaffolding GPCRs with Src kinases and mediating GPCR activation of ERK (42) as well as NFB (43).…”

Section: Discussionmentioning

confidence: 93%

Activation of Nuclear Factor κB by Somatostatin Type 2 Receptor in Pancreatic Acinar AR42J Cells Involves Gα14 and Multiple Signaling Components

Liu

Wong

2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Somatostatin is an endogenous regulatory peptide secreted by a wide range of tissues including neuroendocrine, inflammatory, and immune cells to inhibit the release of various hormones and growth hormones. These inhibitory actions are mediated through heptahelical transmembrane G protein-coupled receptors (GPCRs).2 To date, five distinct subtypes of somatostatin receptors (SSTRs) have been cloned (1). Among the various subtypes, the type 2 somatostatin receptor (SSTR2) has been studied extensively because of its broad clinical applications. Somatostatin analogs targeting SSTR2 have been used as treatments for rheumatoid arthritis, cystitis and other inflammatory diseases (2). Moreover, somatostatin-related compounds hold promise against pancreatic diseases. Abundant SSTR2 expressions are generally detected from cells with pancreatic inflammatory and tumoral diseases (3). In fact, somatostatin administration has been shown to relieve the severities of acute pancreatitis (4), pancreatic adenocarcinoma, and carcinoids (5).As a G i/o -coupled receptor, SSTR2 inhibits adenylyl cyclase and regulates several subsets of K ϩ channels and voltage-dependent Ca 2ϩ channels upon agonist binding. Furthermore, modulation of the activities of tyrosine phosphatase and mitogen-activated protein kinases (MAPKs) by SSTR2 has been well documented (1). Recent studies suggest that SSTR2 can also employ other G proteins such as G 14 and G 16 for signal transduction (6, 7). Its ability to interact functionally with G␣ 14 is particularly interesting. G␣ 14 is a member of the G q family and has more than 80% homology with G␣ q . Upon activation by SSTR2, G␣ 14 stimulates phospholipase C␤ (PLC␤) activity and the production of inositol trisphosphate. Unlike ubiquitously expressed G␣ q/11 proteins, G␣ 14 is expressed predominantly in pancreas, spleen, lung, kidney, testis, bone marrow, several early myeloid and progenitor B cells (8), and many of these tissues also express SSTR2 (1); its mRNA has been detected in normal pancreatic islets (9) as well as tumoral pancreatic acinar cells (10). Signaling via G␣ 14 may provide SSTR2 with the capacity to alter gene expression through the activation of kinases and transcription factors. G 14 -coupled opioid receptors, close relatives of SSTR2, have been shown to activate c-Jun N-terminal kinases (JNKs) (11) and the signal transducer and activator of transcription 3 (STAT3) (12). Although the upstream cellular signals of SSTR2 have been delineated, the mechanism underlying the antiinflammatory and antitumoral effects of somatostatin remains poorly understood. One possible mechanism may involve nuclear factor-B (NFB), a ubiquitous heterodimeric transcription factor that regulates inflammation and cell survival and differentiation (13). In the inactive state, NFB is anchored to inhibitor B␣ (IB␣) in the cytosol. Upon activation, a key regulatory complex, IB kinase (IKK), comprising two catalytic subunits (IKK␣ and IKK␤) and a linker (IKK␥/NEMO) is stimulated by phosphoryla-* This work was supported in ...

show abstract

c-Src Is Activated by the Epidermal Growth Factor Receptor in a Pathway That Mediates JNK and ERK Activation by Gonadotropin-releasing Hormone in COS7 Cells

Cited by 69 publications

References 70 publications

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

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

Neuropeptide-induced Transactivation of a Neuronal Epidermal Growth Factor Receptor Is Mediated by Metalloprotease-dependent Formation of Heparin-binding Epidermal Growth Factor

Activation of Nuclear Factor κB by Somatostatin Type 2 Receptor in Pancreatic Acinar AR42J Cells Involves Gα14 and Multiple Signaling Components

Contact Info

Product

Resources

About