Single Transmembrane Spanning Heterotrimeric G Protein-Coupled Receptors and Their Signaling Cascades

Patel, Tarun B.

doi:10.1124/pr.56.3.4

Cited by 101 publications

(94 citation statements)

References 174 publications

(184 reference statements)

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“…Two principal mechanisms have been advanced to account for the phenomenon. The first proposal is that the receptors possess the ability to directly catalyze heterotrimeric G protein guanine nucleotide exchange (32). Consistent with this, several groups have reported that heterotrimeric G protein subunits co-precipitate with the IGF-1 and insulin receptors (22,23,25) or have demonstrated that small peptides derived from the insulin and IGF-2 receptors promote a mastoparan-like acceleration of GTP exchange on purified heterotrimeric G proteins in vitro (31,(33)(34)(35).…”

mentioning

confidence: 63%

“…Although to date only seven membrane-spanning receptors have been shown to possess ligand-activated guanine nucleo- tide exchange factor activity for heterotrimeric G proteins in purified reconstituted systems, it is nonetheless clear that numerous nonheptahelical receptors signal in part through G protein activation (32). Despite the apparent generality of the phenomenon, the mechanisms underlying G protein activation by these receptors remain poorly understood.…”

Section: Discussionmentioning

confidence: 96%

“…Despite the apparent generality of the phenomenon, the mechanisms underlying G protein activation by these receptors remain poorly understood. Some evidence suggests that the heptahelical GPCR architecture is not required for a receptor to directly catalyze heterotrimeric G protein activation (32). For example, G␣ i and G␤ subunits have been shown to co-precipitate with the IGF-1 receptor, and IGF-1 stimulation reportedly increases the amount of receptorassociated G␣ i while decreasing the amount of bound G␤ (22,23).…”

Section: Discussionmentioning

confidence: 99%

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Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

El‐Shewy¹,

Johnson²,

Lee³

et al. 2006

J. Biol. Chem.

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Although several studies have shown that a subset of insulin-like growth factor (IGF) signals require the activation of heterotrimeric G proteins, the molecular mechanisms underlying IGF-stimulated G protein signaling remain poorly understood. Here, we have studied the mechanism by which endogenous IGF receptors activate the ERK1/2 mitogen-activated protein kinase cascade in HEK293 cells. In these cells, treatment with pertussis toxin and expression of a G␣ q/11 -(305-359) peptide that inhibits G q/11 signaling additively inhibited IGF-stimulated ERK1/2 activation, indicating that the signal was almost completely G protein-dependent. Treatment with IGF-1 or IGF-2 promoted translocation of green fluorescent protein (GFP)-tagged sphingosine kinase (SK) 1 from the cytosol to the plasma membrane, increased endogenous SK activity within 30 s of stimulation, and caused a statistically significant increase in intracellular and extracellular sphingosine 1-phosphate (S1P) concentration. Using a GFP-tagged S1P 1 receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that IGF-1 and IGF-2 induced GFP-S1P receptor internalization and that the effect was blocked by pretreatment with the SK inhibitor, dimethylsphingosine. Treating cells with dimethylsphingosine, silencing SK1 expression by RNA interference, and blocking endogenous S1P receptors with the competitive antagonist VPC23019 all significantly inhibited IGF-stimulated ERK1/2 activation, suggesting that IGFs elicit G protein-dependent ERK1/2 activation by stimulating SK1-dependent transactivation of S1P receptors. Given the ubiquity of SK and S1P receptor expression, S1P receptor transactivation may represent a general mechanism for G protein-dependent signaling by non-G protein-coupled receptors.The insulin-like growth factors type 1 and 2 (IGF-1 and -2) 2 are single chain polypeptides that share structural homology with proinsulin. The actions of IGF-1 and IGF-2 are mediated by binding to two structurally distinct plasma membrane receptors, referred to as the IGF-1 and IGF-2/mannose 6-phosphate (M6P) receptors. Most of the metabolic and mitogenic effects of IGF-1 and IGF-2 are thought to result from binding to the IGF-1 receptor, a receptor tyrosine kinase with structural homology to the insulin receptor. It is composed of two extracellular ␣ subunits and two transmembrane ␤ subunits linked by disulfide bonds (1, 2). Ligand binding to the ␣ subunits activates the intrinsic ␤ subunit receptor tyrosine kinase activity, leading to tyrosine phosphorylation of adapter proteins, such as insulin receptor substrate 1 (IRS-1) and Shc and Gab1 (3-6). Subsequent src homology 2 or protein tyrosine-binding domaindependent recruitment of enzymes with phospholipase, phosphatase, and protein and lipid kinase activity transmits signals intracellularly, including activation of the mitogenic Ras cascade and initiation of phosphatidylinositol 3-kinase (PI3K)/Aktdependent cell survival. Adding to the diversity, in some cell types IGF-1 stimula...

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mentioning

confidence: 63%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

El‐Shewy¹,

Johnson²,

Lee³

et al. 2006

J. Biol. Chem.

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“…Nonetheless, it is clear that heterotrimeric G proteins mediate a subset of signals initiated by diverse non-heptahelical receptors, including the insulin, IGF-1, EGF, and platelet-derived growth factor receptor tyrosine kinases and single membrane-spanning receptors for C-type natriuretic peptide and zona pellucida glycoprotein, integrins, and T cell receptors (49). Apart from our results with the IGF-1 and IGF-2/M6P receptors (31), heterotrimeric G protein activation resulting from SK1-dependent transactivation of S1P receptors has been shown to account for pertussis toxin-sensitive signaling by plateletderived growth factor receptor (50,51).…”

Section: Discussionmentioning

confidence: 99%

The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells

El‐Shewy

Lee

Obeid

et al. 2007

Journal of Biological Chemistry

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Insulin-like growth factor types 1 and 2 (IGF-1; IGF-2) and insulin-like peptides are all members of the insulin superfamily of peptide hormones but bind to several distinct classes of membrane receptor. Like the insulin receptor, the IGF-1 receptor is a heterotetrameric receptor tyrosine kinase, whereas the IGF-2/ mannose 6-phosphate receptor is a single transmembrane domain protein that is thought to function primarily as clearance receptors. We recently reported that IGF-1 and IGF-2 stimulate the ERK1/2 cascade by triggering sphingosine kinasedependent "transactivation" of G protein-coupled sphingosine-1-phosphate receptors. To determine which IGF receptors mediate this effect, we tested seven insulin family peptides, IGF-1, IGF-2, insulin, and insulin-like peptides 3, 4, 6, and 7, for the ability to activate ERK1/2 in HEK293 cells. Only IGF-1 and IGF-2 potently activated ERK1/2. Although IGF-2 was predictably less potent than IGF-1 in activating the IGF-1 receptor, they were equipotent stimulators of ERK1/2. Knockdown of IGF-1 receptor expression by RNA interference reduced the IGF-1 response to a greater extent than the IGF-2 response, suggesting that IGF-2 did not signal exclusively via the IGF-1 receptor. In contrast, IGF-2 receptor knockdown markedly reduced IGF-2-stimulated ERK1/2 phosphorylation, with no effect on the IGF-1 response. As observed previously, both the IGF-1 and the IGF-2 responses were sensitive to pertussis toxin and the sphingosine kinase inhibitor, dimethylsphingosine. These data indicate that endogenous IGF-1 and IGF-2 receptors can independently initiate ERK1/2 signaling and point to a potential physiologic role for IGF-2 receptors in the cellular response to IGF-2.The insulin superfamily family of peptide hormones, consisting of insulin, insulin-like growth factor type 1 (IGF-1), 2 insu- Although all members of the insulin superfamily share structural homology, their signals are transmitted through binding to a number of structurally dissimilar receptors. IGF-1 and IGF-2 are single chain polypeptides, with sequences 62% identical to that of proinsulin. Both contain a short D domain that is not present in insulin, and unlike insulin, they do not undergo post-translational proteolysis, such that the A and B domains remain linked in the mature peptide by a C domain analogous to the C peptide of insulin (1, 2). IGF-1 and IGF-2 bind two structurally distinct types of receptor, referred to as the IGF-1 and IGF-2/mannose-6-phosphate (M6P) receptors. The IGF-1 receptor is heterotetrameric transmembrane receptor tyrosine kinase that is structurally and functionally related to the insulin receptor. It is composed of two extracellular ␣-subunits that contain the ligand-binding domain and two transmembrane ␤-subunits that possess intrinsic ligand-stimulated tyrosine kinase activity (3,4). Ligand binding to the ␣-subunit activates the ␤-subunit tyrosine kinase, resulting in tyrosine phosphorylation of intracellular adapter proteins, such as insulin receptor substrate (IRS)-1 and IRS-2, Shc, and...

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“…Signaling events have been considered to act through cell surface receptors to transduce cytosolic signals via the actions of tyrosine and serine/threonine kinases, or by eliciting 'second messengers' such as Ca þ 2 and cAMP. [1][2][3] However, a relatively new concept termed 'dependence' has been applied to a growing number of receptors. 4 Dependence receptors, generally, maintain the capacity to elicit cell signaling events similar to the 'classic' receptors, but also maintain a capacity to signal 'negatively' in the absence of their cognate ligand.…”

Section: Introductionmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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Single Transmembrane Spanning Heterotrimeric G Protein-Coupled Receptors and Their Signaling Cascades

Cited by 101 publications

References 174 publications

Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors

The Insulin-like Growth Factor Type 1 and Insulin-like Growth Factor Type 2/Mannose-6-phosphate Receptors Independently Regulate ERK1/2 Activity in HEK293 Cells

Integrins as a distinct subtype of dependence receptors

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