Coupling of Heterotrimeric Gi Proteins to the Erythropoietin Receptor

Guillard, Christine; Chrétien, Stany; Jockers, Ralf; Fichelson, Serge; Mayeux, Patrick; Duprez, Véronique

doi:10.1074/jbc.m003527200

Cited by 17 publications

(18 citation statements)

References 72 publications

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“…To generate the ⌬V-L EpoR mutant lacking residues Val-469 to Leu-475 within the intracellular domain, mutation was introduced into the full-length EpoR by PCR. The PCR product was digested with HindIII/ XbaI and subcloned into the same restriction sites of a modified pCDNA3 expression vector (15). The fidelity of all constructs was confirmed by sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…The murine EpoR mutant Ϫ41 was described previously (15). To generate the ⌬V-L EpoR mutant lacking residues Val-469 to Leu-475 within the intracellular domain, mutation was introduced into the full-length EpoR by PCR.…”

Section: Methodsmentioning

confidence: 99%

“…ADP-ribosylation Assay-To detect G␣ i its ADP-ribosylation was followed by measuring incorporation of [ 32 P]ADP-ribose in the presence of pertussis toxin in vitro as previously described (15).…”

Section: Methodsmentioning

confidence: 99%

“…The G i -EpoR interaction occurs through the C-terminal end of the cytoplasmic domain of the receptor. After Epo activation the G i protein is activated and released from the receptor, most likely with the concomitant dissociation of G i ␣ and ␤␥ subunits (15).…”

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confidence: 99%

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Activation of the Mitogen-activated Protein Kinases Erk1/2 by Erythropoietin Receptor via a Gi Protein βγ-Subunit-initiated Pathway

Guillard

Chrétien

Pelus

et al. 2003

Journal of Biological Chemistry

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We have recently shown that a heterotrimeric G i protein is coupled to the erythropoietin (Epo) receptor. The G i protein constitutively associates in its heterotrimeric form with the intracellular domain of Epo receptor (EpoR). After Epo stimulation G i is released from the receptor and activated. In the present study we have investigated the functional role of the heterotrimeric G i protein bound to EpoR. In Chinese hamster ovary cells expressing EpoR, the G i inhibitor pertussis toxin blocked mitogen-activated protein kinase (MAPK) Erk1/2 activation induced by Epo. Epo-dependent MAPK activation was also sensitive to the G␤␥ competitive inhibitor ␤ARK1-ct (C-terminal fragment of the ␤-adrenergic receptor kinase), to the Ras dominant negative mutant RasN17, and to the phosphoinositide 3-kinase (PI3K) inhibitor LY 294002. A region of 7 amino acids (469 -475) in the C-terminal end of EpoR was shown to be required for G i binding to EpoR in vivo. Deletion of this region in EpoR abolished both MAPK and PI3K activation in response to Epo. We conclude that in Chinese hamster ovary cells, Epo activates MAPK via a novel pathway dependant on G i association to EpoR, G␤␥ subunit, Ras, and PI3K. The tyrosine kinase Jak2 also contributes to this new pathway, more likely downstream of ␤␥ and upstream of Ras and PI3K. This pathway is similar to the best characterized pathway used by seven transmembrane receptors coupled to G i to activate MAPK and may cooperate with other described Epo-dependent MAPK activation pathways in hematopoietic cells.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Activation of the Mitogen-activated Protein Kinases Erk1/2 by Erythropoietin Receptor via a Gi Protein βγ-Subunit-initiated Pathway

Guillard

Chrétien

Pelus

et al. 2003

Journal of Biological Chemistry

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“…Whether there is a direct coupling between GM-CSFR and G␣ i2 remains to be investigated. In the case of the EPOR, Guillard et al (2001) discovered a novel EPO-dependent MAPK activation pathway involving the G␤␥ subunit of G i proteins. EPO treatment inhibited ADP-ribosylation of G␣ i and increased its binding of GTP.…”

Section: Role Of G␣ Proteins In Transmembrane Signaling Through Othermentioning

confidence: 99%

Heterotrimeric G Protein Signaling Outside the Realm of Seven Transmembrane Domain Receptors

Marty¹,

Ye²

2010

Mol Pharmacol

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Heterotrimeric G proteins, consisting of the guanine nucleotidebinding G␣ subunits with GTPase activity and the closely associated G␤ and G␥ subunits, are important signaling components for receptors with seven transmembrane domains (7TMRs). These receptors, also termed G protein-coupled receptors (GPCRs), act as guanine nucleotide exchange factors upon agonist stimulation. There is now accumulating evidence for noncanonical functions of heterotrimeric G proteins independent of 7TMR coupling. G␣ proteins belonging to all 4 subfamilies, including G s , G i , G q , and G 12 are found to play important roles in receptor tyrosine kinase signaling, regulation of oxidant production, development, and cell migration, through physical and functional interaction with proteins other than 7TMRs. Association of G␣ with non-7TMR proteins also facilitates presentation of these G proteins to specific cellular microdomains. This Minireview aims to summarize our current understanding of the noncanonical roles of G␣ proteins in cell signaling and to discuss unresolved issues including regulation of G␣ activation by proteins other than the 7TMRs.

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Signal Transduction Mediated by Heptahelical Receptors and Heterotrimeric G Proteins

Hébert

Northup

Rebois

2006

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Coupling of Heterotrimeric Gi Proteins to the Erythropoietin Receptor

Cited by 17 publications

References 72 publications

Activation of the Mitogen-activated Protein Kinases Erk1/2 by Erythropoietin Receptor via a Gi Protein βγ-Subunit-initiated Pathway

Activation of the Mitogen-activated Protein Kinases Erk1/2 by Erythropoietin Receptor via a Gi Protein βγ-Subunit-initiated Pathway

Heterotrimeric G Protein Signaling Outside the Realm of Seven Transmembrane Domain Receptors

Signal Transduction Mediated by Heptahelical Receptors and Heterotrimeric G Proteins

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