Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

Tao, Ya-Xiong

doi:10.1016/j.pharmthera.2008.07.005

Cited by 146 publications

(113 citation statements)

References 332 publications

(348 reference statements)

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“…However, in this study, alanine mutation of D178 3.49 A and Y189 3.60 A had no effect on the basal activity of MC3R, implying that such hydrogen bonding interactions do not exist or do not affect the basal activity of MC3R. There is usually a correlation between the basal activity of the WT receptor and the propensity of mutations to be constitutively active (Tao et al 2002, Tao 2008. As MC3R basal activity is low, the propensity of MC3R mutations to be constitutively active is probably low.…”

Section: Discussioncontrasting

confidence: 52%

Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Huang¹,

Tao²

2014

Journal of Molecular Endocrinology

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The melanocortin 3 receptor (MC3R) regulates several physiological functions, including feed efficiency, nutrient partitioning, fasting response, natriuresis, and immune reactions. Naturally occurring mutations in the MC3R gene have been shown to be associated with increased adiposity and lung diseases such as tuberculosis and cystic fibrosis. The DRY motif at the cytoplasmic end of transmembrane domain 3 (TM3) and the second intracellular loop 2 (ICL2) are known to be important for receptor function in several G protein-coupled receptors (GPCRs). To gain a better understanding of the functions of this domain in MC3R, we performed alanine-scanning mutagenesis on 18 residues. We showed that alanine mutation of 11 residues reduced the maximal binding and maximal cAMP production stimulated by agonists. Mutation of two residues did not change maximal binding but resulted in impaired signaling in the G s -cAMP pathway. Mutation of five residues impaired signaling in the ERK1/2 pathway. We have also shown that alanine mutants of seven residues that were defective in the cAMP pathway were not defective in the ERK1/2 pathway, demonstrating biased signaling. In summary, we demonstrated that the cytoplasmic end of TM3 and the ICL2 were critical for MC3R function. We also reported for the first time biased signaling in MC3R. Key Words" melanocortin 3 receptor " intracellular loop 2 " DRY motif " MAP kinase " biased signaling

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Section: Discussioncontrasting

confidence: 52%

Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Huang¹,

Tao²

2014

Journal of Molecular Endocrinology

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“…So-called "constitutively activating" mutations and their gene products contribute to a broad range of clinical conditions ranging from cancer to syndromic developmental defects, including inborn disorders of metabolism, endocrine abnormalities, and sensory defects (1)(2)(3). Constitutively activating mutations, commonly referred to as "gain-offunction" mutations, can augment function in multiple ways.…”

mentioning

confidence: 99%

Constitutively Active ALK2 Receptor Mutants Require Type II Receptor Cooperation

et al. 2013

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f Constitutively activating mutations in receptor kinases recruit downstream effector pathways independently of upstream signaling, with consequences ranging from developmental syndromes to cancer. Classic fibrodysplasia ossificans progressiva (FOP) is a congenital syndrome resulting from highly conserved activating mutations of the glycine-serine-rich (GS) regulatory domain of ACVR1, encoding bone morphogenetic protein (BMP) type I receptor ALK2, which lead to inappropriate signaling and heterotopic ossification of soft tissues. It is unclear if constitutively active mutant ALK2 receptors (caALK2) can function independently of signaling complexes with type II receptors and ligands. We found that ablation of BmpRII and ActRIIa abrogated BMP ligand-mediated and caALK2-mediated signaling and transcription in cells and disrupted caALK2-induced heterotopic ossification in mice. Signaling via GS domain ALK2 mutants could be restored by the expression of either BMP type II receptor. The contribution of BMP type II receptors was independent of their ligand-binding or kinase function but was dependent upon an intact cytoplasmic domain. These data demonstrate that GS domain ALK2 mutants act independently of upstream signaling but may require a nonenzymatic scaffolding function provided by type II receptors to form functional, apparently ligand-independent signaling complexes. These findings define the minimal requirements for signaling of GS domain ALK2 mutants, with implications for the therapeutic targeting of their activity in disease. In human disease, somatic or germ line mutations may confer "constitutive" activity to mutant signaling or receptor proteins, permitting the recruitment of downstream effectors independently of upstream signaling events. So-called "constitutively activating" mutations and their gene products contribute to a broad range of clinical conditions ranging from cancer to syndromic developmental defects, including inborn disorders of metabolism, endocrine abnormalities, and sensory defects (1-3). Constitutively activating mutations, commonly referred to as "gain-offunction" mutations, can augment function in multiple ways. Constitutively active mutant receptor proteins may have true constitutive activity that is invariant with stimuli, harbor activity that is hypersensitive or amplified in response to native ligands, or have activity that can be induced with decreased specificity (4).Fibrodysplasia ossificans progressiva (FOP) is a congenital heterotopic ossification (HO) disorder in which afflicted individuals are nearly normal at birth except for subtle skeletal malformations yet are prone to forming endochondral bone lesions in soft tissues such as skeletal muscle, ligaments, and fascia, especially following injury or inflammation (5). The classic FOP phenotype results from highly conserved activating mutations in ACVR1, encoding the bone morphogenetic protein (BMP) type I receptor kinase ALK2, due to an R206H substitution in the glycine-serine-rich (GS) regulatory domain (6, 7). While other...

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“…Two SDMs (L140G and L140R) had similar levels of ERK1/2 phosphorylation as that of WT MC4R upon NDP-MSH stimulation, different from their cAMP signaling properties. It is interesting to note that although L140R had decreased basal cAMP activity (see also Tao (2008)), it had significant constitutive pERK1/2 levels (Fig. 11C).…”

Section: Signaling Properties Of L140 Mutants At the Erk1/2 Pathwaymentioning

confidence: 80%

Functions of transmembrane domain 3 of human melanocortin-4 receptor

Mo¹,

Yang²,

Tao³

2012

Journal of Molecular Endocrinology

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The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor critical for maintaining energy homeostasis. Transmembrane domain 3 (TM3) of MC4R contains residues that were suggested to be essential in ligand binding and signaling. Several MC4R mutations in TM3 are associated with human obesity. To gain a better understanding of the functions of TM3, we analyzed the functions of 26 residues in TM3 using alanine-scanning mutagenesis. We showed that all mutants had normal cell-surface expression. Four mutants were defective in ligand binding and signaling and six mutants had normal ligand binding but impaired cAMP production. L140A had increased basal cAMP level. To further characterize the function of L140, we generated 17 additional L140 mutants. Fifteen L140 mutants had significantly decreased cell-surface expression, with L140R and L140V expressed normally. Ten L140 mutants had increased basal cAMP activities. Four L140 mutants were defective in ligand-stimulated cAMP generation. Interestingly, with the ERK1/2 pathway, we showed that nine constitutively active mutants had similar levels of basal pERK1/2 as that of WT, and two signaling defective mutants had similar levels of pERK1/2 as that of WT upon agonist stimulation, different from their cAMP signaling properties, suggesting biased signaling in these mutant receptors. In summary, we identified 13 residues in TM3 that were essential for ligand binding and/or signaling. Moreover, L140 was critical for locking MC4R in inactive conformation and several mutants showed biased signaling in cAMP and ERK1/2 signaling pathways.

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Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics

Cited by 146 publications

References 332 publications

Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Constitutively Active ALK2 Receptor Mutants Require Type II Receptor Cooperation

Functions of transmembrane domain 3 of human melanocortin-4 receptor

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