Gβγ Subunits Mediate Mitogen-activated Protein Kinase Activation by the Tyrosine Kinase Insulin-like Growth Factor 1 Receptor

Luttrell, Louis M.; Biesen, Tim van; Hawes, Brian E.; Koch, Walter J.; Touhara, Kazushige; Lefkowitz, Robert J.

doi:10.1074/jbc.270.28.16495

Cited by 199 publications

(167 citation statements)

References 39 publications

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“…The involvement of G i in regulating growth-factor-receptor signalling is supported by studies from Luttrell and colleagues [8]. These authors showed that PTX and an inhibitor of G i βγ-mediated signalling (C-terminal domain of β-adrenergic receptor kinase) blocked the activation of p42\p44 MAPK by insulin and insulin-like-growth-factor-1 receptors in rat 1A fibroblasts.…”

Section: Role Of C-srcmentioning

confidence: 88%

“…There are two exceptions, namely insulin and insulin-like-growth-factor-1 receptor, which stimulate p42\ p44 MAPK activation in a pertussis toxin (PTX)-sensitive manner in fibroblasts [8]. In contrast, there is a growing body of evidence to suggest that G i -coupled receptor agonists can stimulate growth-factor-receptor transactivation [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

Conway

Rakhit

Pyne

et al. 1999

Biochemical Journal

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The mechanism used by the platelet-derived growth factor receptor (PDGFR) to activate the mitogen-activated-proteinkinase (p42\p44 MAPK) pathway was investigated in cultured airway smooth muscle (ASM) cells. We have found that pertussis toxin (PTX, which was used to inactivate the heterotrimeric Gprotein G i ) induced an approx. 40-50 % decrease in the activation of c-Src and p42\p44 MAPK by PDGF. An essential role for c-Src was confirmed using the c-Src inhibitor, PP1, which abolished p42\p44 MAPK activation (PP1 and PTX were without effect on PDGFR tyrosine phosphorylation). Furthermore, the PTX-dependent decrease in c-Src and p42\p44 MAPK activation appeared correlated. These findings suggest that the PDGFR can utilize the PTX-sensitive G-protein, G i , to regulate c-Src and subsequent p42\p44 MAPK activation. Phosphoinositide 3-kinase (PI3K) has been shown by others to be involved in p42\p44 MAPK activation. This is confirmed here

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Section: Role Of C-srcmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

Conway

Rakhit

Pyne

et al. 1999

Biochemical Journal

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“…The IGF-IR activates heterotetrameric G proteins in certain cell types. It has been reported that the βγ subunits of the Gi class of G proteins can mediate IGF-I-induced activation of MAP kinase (Luttrell et al, 1995). In addition, it has been demonstrated that the IGF-IR forms a complex with the Gα subunit of Gi proteins (Dalle et al, 2001).…”

Section: Receptor Cross-talkmentioning

confidence: 99%

The Insulin‐Like Growth Factor System

Roith

2003

Journal of Diabetes Research

165

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The insulin-like growth factor (IGF) system in ubiquitous and plays a role in every tissue of the body. It is comprised of ligands, receptors and binding proteins, each with specific functions. While it plays an essential role in embryonic and post-natal development, the IGF system is also important in normal adult physiology. There are now numerous examples of diseases such as diabetes, cancer, and malnutrition in which the IGF system is a major player and, not surprisingly, there are attempts to affect these disorders by manipulating the system.

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“…To verify that this dose of PTX will inactivate G i , we determined whether PTX could block LPA signaling in hIRcB cells. LPA has been shown to signal through the G i heterotrimeric protein leading to G␤␥-mediated activation of MAPK (30). Pretreatment of cells with PTX reduced ERK activation in response to 10 M LPA by immunoblotting, whereas activation by insulin was unaffected ( Fig.…”

Section: Gnrh-mediated Signaling Is Pertussis Toxin-insensitive In L␤t2mentioning

confidence: 99%

“…Expression of Fusion Proteins-The ␤ARK-CT fusion protein was purified as a GST fusion protein as described previously (30). For the TAT fusion peptides, oligonucleotides encoding the G q -CT (QLNLKEYNLV), G s -CT (RMHLRQYELL), or PLC␤2 (NRSYVISSFTELKAYDLLSK) peptides were cloned into expression vector pTAT-HA (31).…”

Section: Methodsmentioning

confidence: 99%

Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LβT2 Cells

Liu¹,

Usui²,

Evans³

et al. 2002

Journal of Biological Chemistry

174

125

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The hypothalamic hormone gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of the pituitary gonadotropins. GnRH acts through a plasma membrane receptor that is a member of the G protein-coupled receptor (GPCR) family. These receptors interact with heterotrimeric G proteins to initiate downstream signaling. In this study, we have investigated which G proteins are involved in GnRH receptormediated signaling in L␤T2 pituitary gonadotrope cells. We have shown previously that GnRH activates ERK and induces the c-fos and LH␤ genes in these cells. Signaling via the G i subfamily of G proteins was excluded, as neither ERK activation nor c-Fos and LH␤ induction was impaired by treatment with pertussis toxin or a cell-permeable peptide that sequesters G␤␥-subunits. GnRH signaling was partially mimicked by adenoviral expression of a constitutively active mutant of G␣ q (Q209L) and was blocked by a cell-permeable peptide that uncouples G␣ q from GPCRs. Furthermore, chronic activation of G␣ q signaling induced a state of GnRH resistance. A cell-permeable peptide that uncouples G␣ s from receptors was also able to inhibit ERK, c-Fos, and LH␤, indicating that both G q/11 and G s proteins are involved in signaling. Consistent with this, GnRH caused GTP loading on G s and G q/11 and increased intracellular cAMP. Artificial elevation of cAMP with forskolin activated ERK and caused a partial induction of c-Fos. Finally, treatment of G␣ q (Q209L)-infected cells with forskolin enhanced the induction of c-Fos showing that the two pathways are independent and additive. Taken together, these results indicate that the GnRH receptor activates both G q and G s signaling to regulate gene expression in L␤T2 cells.The family of G protein-coupled receptors is the largest and most complex group of integral membrane proteins involved in signal transduction. These receptors can be activated by a diverse array of external stimuli, including growth factors, neurotransmitters, peptide, and protein hormones, chemokines, and other ligands. Agonist binding to a specific receptor on the cell surface causes a conformational change in the receptor that allows it to interact with its cognate G protein, stimulating guanine nucleotide exchange on the ␣-subunit of the G protein. The release of the GTP-bound ␣-subunit and ␤␥-subunits from the receptor-G protein complex initiates a broad range of intracellular signaling events, including the activation of classical effectors such as phospholipase C, adenylate cyclases, and ion channels, and regulation of the intracellular level of inositol phosphates, calcium, cyclic AMP, and other second messengers (for reviews see Refs. 1-8).Gonadotropin-releasing hormone (GnRH) 1 is a hypothalamic decapeptide, which serves as a key regulator of the reproductive system. In the pituitary, GnRH signals are transmitted via a specific cell surface receptor, which is a member of the G protein-coupled receptor superfamily. When GnRH binds to its receptor, it induces interaction of the receptor with heterot...

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Gβγ Subunits Mediate Mitogen-activated Protein Kinase Activation by the Tyrosine Kinase Insulin-like Growth Factor 1 Receptor

Cited by 199 publications

References 39 publications

Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

The Insulin‐Like Growth Factor System

Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LβT2 Cells

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