scholarly journals Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase

2001 ◽  
Vol 114 (6) ◽  
pp. 1213-1220
Author(s):  
D. Nath ◽  
N.J. Williamson ◽  
R. Jarvis ◽  
G. Murphy
Keyword(s):  
Growth Factor ◽  
G Protein ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Receptor Activation ◽  
Ectodomain Shedding ◽  
G Protein Coupled Receptor ◽  
Cell Matrix ◽  
Cell Matrix Interactions ◽  
G Protein Coupled

A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as ‘ectodomain shedding’, under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.

scholarly journals The Platelet-derived Growth Factor Receptor-β Phosphorylates and Activates G Protein-coupled Receptor Kinase-2

2005 ◽  
Vol 280 (35) ◽  
pp. 31027-31035 ◽  
Author(s):  
Jiao-Hui Wu ◽  
Robi Goswami ◽  
Luke K. Kim ◽  
William E. Miller ◽  
Karsten Peppel ◽  
...  
Keyword(s):  
Growth Factor ◽  
G Protein ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Estrogen Action Via the G Protein-Coupled Receptor, GPR30: Stimulation of Adenylyl Cyclase and cAMP-Mediated Attenuation of the Epidermal Growth Factor Receptor-to-MAPK Signaling Axis

2002 ◽  
Vol 16 (1) ◽  
pp. 70-84 ◽  
Author(s):  
Edward J. Filardo ◽  
Jeffrey A. Quinn ◽  
A. Raymond Frackelton ◽  
Kirby I. Bland
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Adenylyl Cyclase ◽  
G Protein ◽  
Egf Receptor ◽  
G Protein Coupled Receptor ◽  
Estrogen Action ◽  
Epidermal Growth ◽  
G Protein Coupled ◽  
Stimulation Of

Abstract Estrogen triggers rapid yet transient activation of the MAPKs, extracellular signal-regulated kinase (Erk)-1 and Erk-2. We have reported that this estrogen action requires the G protein-coupled receptor, GPR30, and occurs via Gβγ-subunit protein-dependent transactivation of the epidermal growth factor (EGF) receptor through the release of pro-heparan-bound EGF from the cell surface. Here we investigate the mechanism by which Erk-1/-2 activity is rapidly restored to basal levels after estrogen stimulation. Evidence is provided that attenuation of Erk-1/-2 activity by estrogen occurs via GPR30-dependent stimulation of adenylyl cyclase and cAMP-dependent signaling that results in Raf-1 inactivation. We show that 17β-E2 represses EGF-induced activation of the Raf-to-Erk pathway in human breast carcinoma cells that express GPR30, including MCF-7 and SKBR3 cells which express both or neither, ER, respectively. MDA-MB-231 cells, which express ERβ, but not ERα, and low levels of GPR30 protein, are unable to stimulate adenylyl cyclase or promote estrogen-mediated blockade of EGF-induced activation of Erk-1/-2. Pretreatment of MDA-MB-231 cells with cholera toxin, which ADP-ribosylates and activates Gαs subunit proteins, results in G protein-coupled receptor (GPCR)-independent adenylyl cyclase activity and suppression of EGF-induced Erk-1/-2 activity. Transfection of GPR30 into MDA-MB-231 cells restores their ability to stimulate adenylyl cyclase and attenuate EGF-induced activation of Erk-1/-2 by estrogen. Moreover, GPR30-dependent, cAMP-mediated attenuation of EGF-induced Erk-1/-2 activity was achieved by ER antagonists such as tamoxifen or ICI 182, 780; yet not by 17α-E2 or progesterone. Thus, our data delineate a novel mechanism, requiring GPR30 and estrogen, that acts to regulate Erk-1/-2 activity via an inhibitory signal mediated by cAMP. Coupled with our prior findings, these current data imply that estrogen balances Erk-1/-2 activity through a single GPCR via two distinct G protein-dependent signaling pathways that have opposing effects on the EGF receptor-to-MAPK pathway.

scholarly journals G protein–coupled receptor kinase 2 (GRK2) is localized to centrosomes and mediates epidermal growth factor–promoted centrosomal separation

2013 ◽  
Vol 24 (18) ◽  
pp. 2795-2806 ◽  
Author(s):  
Christopher H. So ◽  
Allison Michal ◽  
Konstantin E. Komolov ◽  
Jiansong Luo ◽  
Jeffrey L. Benovic
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
G Protein ◽  
Growth Factor Receptor ◽  
Dominant Negative ◽  
G Protein Coupled Receptor ◽  
Microtubule Nucleation ◽  
Epidermal Growth ◽  
G Protein Coupled

G protein–coupled receptor kinases (GRKs) play a central role in regulating receptor signaling, but recent studies suggest a broader role in modulating normal cellular functions. For example, GRK5 has been shown to localize to centrosomes and regulate microtubule nucleation and cell cycle progression. Here we demonstrate that GRK2 is also localized to centrosomes, although it has no role in centrosome duplication or microtubule nucleation. Of interest, knockdown of GRK2 inhibits epidermal growth factor receptor (EGFR)–mediated separation of duplicated centrosomes. This EGFR/GRK2-mediated process depends on the protein kinases mammalian STE20-like kinase 2 (Mst2) and Nek2A but does not involve polo-like kinase 1. In vitro analysis and dominant-negative approaches reveal that GRK2 directly phosphorylates and activates Mst2. Collectively these findings demonstrate that GRK2 is localized to centrosomes and plays a central role in mitogen-promoted centrosome separation most likely via its ability to phosphorylate Mst2.

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