Insulin activates Gαil,2 protein in rat hepatoma (HTC) cell membranes

Sánchez-Margalet, Vı́ctor; González-Yanes, Carmen; Santos‐Álvarez, José; Najib, Souad

doi:10.1007/s000180050279

Cited by 14 publications

(12 citation statements)

References 46 publications

(28 reference statements)

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“…First, IGF-IR, similar to a canonical GPCR, could directly interact with and activate the G proteins (Sanchez-Margalet et al 1999, Hallak et al 2000, Kuemmerle & Murthy 2001. Stimulated insulin receptor, an IGF-IR family member, was reported to catalytically activate Gi/o proteins in a manner similar to GPCRs in rat hepatoma cells (SanchezMargalet et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Lyons-Darden

Daaka

2004

Journal of Molecular Endocrinology

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Elevated levels of IGF-I in the circulation are associated with increased risk for the development of prostate cancer in men, and transgenic expression of human IGF-I in mouse epithelial prostate cells results in spontaneous prostate tumorigenesis. Little, however, is known about the mechanisms involved in the IGF-I-regulated growth of prostate cells. Here, we have demonstrated that treatment with IGF-I induces the activation of the mitogenic extracellular signal-regulated kinase (ERK) pathway and the growth of human prostate cells. Stimulation with IGF-I also promoted the tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Signal relay from IGF-I to ERK requires heterotrimeric G proteins and EGFR; inhibition of Gi/o protein activation by pertussis toxin, or EGFR by tyrphostin AG1478 obliterated the ability of IGF-I to promote ERK activation. Further, treatment with pertussis toxin inhibited the IGF-I-mediated prostate cell growth. These data demonstrated the requirement of heterotrimeric G proteins in IGF-I-regulated prostate cell growth and suggest the potential utility of the G proteins as effective drug targets to combat this common cancer.

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Section: Discussionmentioning

confidence: 99%

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Lyons-Darden

Daaka

2004

Journal of Molecular Endocrinology

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“…G ␣i2 and G ␤ (but not G ␣i1 or G ␣i3 ) were identified in purified insulin receptor preparations (14). In a recent study, Sanchez et al (19) reported that activation of the insulin receptor recruits G ␣i to this receptor, in a manner similar to classical GPCRs. However, this differs from our finding that G ␣i constitutively associates with the IGF-IR.…”

Section: Discussionmentioning

confidence: 99%

“…Pertussis toxin inhibits metabolic and mitogenic actions of insulin in a variety of cell culture models (9 -16), and insulin enhances GTP binding to membranes (16,18). In a recent study of rat hepatoma cell membranes (19), antibodies targeted against G ␣i but not G ␣o , prevented insulin-2 H. Hallak, and R. Rubin, unpublished data. stimulated GTP binding.…”

Section: Discussionmentioning

confidence: 99%

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Association of Heterotrimeric Gi with the Insulin-like Growth Factor-I Receptor

Hallak

Seiler

Green

et al. 2000

Journal of Biological Chemistry

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The insulin-like growth factor-I receptor (IGF-IR) is a key regulator of cell proliferation and survival. Activation of the IGF-IR induces tyrosine autophosphorylation and the binding of a series of adaptor molecules, thereby leading to the activation of MAPK. It has been demonstrated that pertussis toxin, which inactivates the G i class of GTP-binding proteins, inhibits IGF-I-mediated activation of MAPK, and a specific role for G ␤␥ subunits in IGF-I signaling was shown. In the present study, we have investigated the role of heterotrimeric G i in IGF-IR signaling in neuronal cells. Pertussis toxin inhibited IGF-I-induced activation of MAPK in rat cerebellar granule neurons and NG-108 neuronal cells. G ␣i and G ␤ subunits were associated with IGF-IR immunoprecipitates. Similarly, in IGF-IR-null mouse embryo fibroblasts transfected with the human IGF-IR, G i was complexed with the IGF-IR. G ␣s was not associated with the IGF-IR in any cell type. IGF-I induced the release of the G ␤ subunits from the IGF-IR but had no effect on the association of G ␣i . These results demonstrate an association of heterotrimeric G i with the IGF-IR and identify a discrete pool of G ␤␥ subunits available for downstream signaling following stimulation with IGF-I.Many receptors are coupled to heterotrimeric GTP-binding proteins (G-proteins). Prototypic G-protein coupled receptors (GPCRs) 1 contain a seven-membrane spanning region (1). Activated GPCRs bind to G-proteins and induce the release of G ␤␥ subunits from G ␣ subunits, which allows for the exchange of GDP for GTP on the G ␣ subunit. Activated G i subunits and G ␤␥ heterodimers interact with numerous signaling effectors, including adenylyl cyclase, ion channels, protein kinases, and phospholipases (2-4).In addition to their role in fully differentiated cells, GPCRs have been linked to mitogenesis and development (5-8). A specific role for G i in the induction of mitogenesis has been highlighted by the use of pertussis toxin, which inactivates G i by ADP-ribosylation of the G ␣ subunit. However, G ␣ subunits from several classes of G-proteins are not strongly mitogenic. Rather G ␤␥ heterodimer subunits activate a series of nonreceptor tyrosine kinases, which in turn activates p21 ras and extracellular signal-regulated kinases (or MAPK). Thus, G ␤␥ subunits serve to bridge intracellular signaling of classical GPCRs and mitogenic tyrosine kinase receptors (RTKs).G i also appears to be involved in the mitogenic actions of RTKs. Pertussis toxin variably inhibits the metabolic actions of insulin, both in vitro and in vivo (9 -16), and the insulin receptor may associate with G i (17)(18)(19). Importantly, mice with targeted knockout of G i have defects in insulin signaling (20). EGF-dependent signaling is also impaired by pertussis toxin in rat hepatocytes (21-23) and other cells (24 -27).The insulin-like growth factor-I receptor (IGF-IR), which has strong homology to the insulin receptor, exists as an ␣ 2 -␤ 2 -heterodimer and contains a cytoplasmic tyrosine kinase domain (28, 29). U...

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“…Pertussis toxin, which inactivates G␣ i family members, has been shown to alter aspects of insulin action (13,14). Members of the G␣ i family have been shown both to be regulated by insulin (15)(16)(17) as well as involved in insulin action (18). Targeted elimination of G␣ i2 in fat, skeletal muscle, and liver in transgenic mice leads to insulin resistance (19 -21).…”

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confidence: 99%

Gαi2 Enhances Insulin Signaling via Suppression of Protein-tyrosine Phosphatase 1B

Tao

Malbon

Wang

2001

Journal of Biological Chemistry

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Suppression of the expression of the heterotrimeric G-protein G␣ i2 in vivo has been shown to provoke insulin resistance, whereas enhanced insulin signaling is observed when G␣ i2 is overexpressed in vivo. The basis for G␣ i2 regulation of insulin signaling was explored in transgenic mice with targeted expression of the GTPasedeficient, constitutively active Q205L G␣ i2 in fat and skeletal muscle. Phosphorylation of insulin receptor and IRS-1 in response to insulin challenge in vivo was markedly amplified in fat and skeletal muscle expressing Q205L G␣ i2 . The expression and activity of the protein-tyrosine phosphatase 1B (PTP1B), but not proteintyrosine phosphatases SHP-1, SHP-2, and LAR, were constitutively decreased in tissues expressing the Q205L G␣ i2 , providing a direct linkage between insulin signaling and G␣ i2 . The loss of PTP1B expression may explain, in part, the loss of PTP1B activity in the iQ205L transgenic mice. Activation of G␣ i2 in mouse adipocytes with lysophosphatidic acid was shown to decrease PTP1B activity, whereas pertussis toxin inactivates G␣ i2 , blocks lysophosphatidic acid-stimulated inhibition of PTP1B activity, and blocks tonic suppression of PTP1B activity by G␣ i2 . Elevation of intracellular cAMP in fat cells is shown to increase PTP1B activity, whereas either depression of cAMP levels or direct activation of G␣ i2 suppresses PTP1B. These data provide the first molecular basis for the interplay between G␣ i2 and insulin signaling, i.e. activation of G␣ i2 can suppress both the expression and activity of PTP1B in insulin-sensitive tissues.

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Insulin activates Gαil,2 protein in rat hepatoma (HTC) cell membranes

Cited by 14 publications

References 46 publications

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Requirement for G proteins in insulin-like growth factor-I-induced growth of prostate cells

Association of Heterotrimeric Gi with the Insulin-like Growth Factor-I Receptor

Gαi2 Enhances Insulin Signaling via Suppression of Protein-tyrosine Phosphatase 1B

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