G protein-coupled receptor cross-talk: pivotal roles of protein phosphorylation and protein?protein interactions

Vázquez‐Prado, José; Casas‐González, Patricia; García‐Sáinz, J. Adolfo

doi:10.1016/s0898-6568(02)00151-1

Cited by 80 publications

(52 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Multiple kinases are known to phosphorylate GPCRs, including GPCR kinases, PKC, and Akt (52). We showed that CXCL12 and EGF treatment, as well as PKC activation, could induce CXCR4 phosphorylation.…”

Section: Discussionmentioning

confidence: 83%

Widespread CXCR4 Activation in Astrocytomas Revealed by Phospho-CXCR4-Specific Antibodies

Woerner¹,

Warrington²,

et al. 2005

View full text Add to dashboard Cite

The chemokine receptor CXCR4 is expressed in many cancers where it may regulate tumor cell growth and migration. The role of CXCR4 in cancer will depend on it being in an activated, signaling state. To better define the significance of CXCR4 expression in cancer, we developed an antibody that can distinguish CXCR4 phosphorylated on serine 339, a residue previously identified as a site for ligand-induced phosphorylation. With this antibody, we investigated the mechanisms of CXCR4 phosphorylation and evaluated the phosphorylation status of CXCR4 in human astrocytomas. In vitro, phosphorylation of serine 339 occurred in response to CXCL12 or epidermal growth factor (EGF) treatment and was increased by protein kinase C activation. In all grades of astrocytomas, CXCR4 was expressed in tumor cells and some endothelial cells, whereas CXCL12 was present in endothelial cells and infiltrating microglia. We found that CXCR4 phosphorylated on serine 339 was present in tumor cells and vascular endothelial cells in all grades of astrocytoma. These data indicate that CXCR4 is expressed and activated in astrocytomas and that phosphorylation of CXCR4 can occur through ligand activation or transactivation via the EGF receptor. These studies extend the potential roles of CXCR4 in cancer to include functions associated with benign (grade 1) tumors. The ability to distinguish phosphorylated CXCR4 will be invaluable for the continued analysis of the role of CXCR4 in cancer and the development of CXCR4 antagonist therapy for patients suffering with primary tumors of the brain and other sites. (Cancer Res 2005; 65(24): 11392-9)

show abstract

Section: Discussionmentioning

confidence: 83%

Widespread CXCR4 Activation in Astrocytomas Revealed by Phospho-CXCR4-Specific Antibodies

Woerner¹,

Warrington²,

et al. 2005

View full text Add to dashboard Cite

show abstract

“…G protein-coupled receptor phosphorylation can be crucial, not only for initiation of G protein signaling but also in desensitization, internalization, downregulation, and cross-talk with other receptors. 28 This remains to be evaluated directly in vitro with this specific mutation. Nonetheless, the cellular and physiological data in this family support the hypothesis that ASP-C5L2 receptor dysfunction leads to altered adipose tissue and metabolic consequences.…”

Section: Discussionmentioning

confidence: 99%

“…This region has been shown to contain important phosphorylation sites associated with activation, desensitization, and downregulation of this class of GPCR. 28 Accordingly, we evaluated the effects of this variant on cellular response to ASP in HSF obtained from three family members (301, 303, and 305 as indicated in Figure 1 and Table 3). ASP has previously been shown to directly stimulate triglyceride synthesis (via fatty acid uptake and esterification) and glucose transport in adipocytes, preadipocytes, 11,12 as well as in HSF.…”

Section: Marcil Et Al Identification Of a Novel C5l2 Variantmentioning

confidence: 99%

“…These experimental data suggest that this variant leads to a functional disruption in signaling consequent to a serine to isoleucine substitution in the carboxyl terminal tail. Serine-threonine clusters in the carboxyl terminal tail of G protein-coupled receptors have been demonstrated to be common phosphorylation sites 28 and, indeed, computer analysis of the C5L2 sequence via Net-Phos (www.cbs.dtu.dk) strongly predicts this serine (S323) as the highest (score 0.997) potential serine phosphorylation site. G protein-coupled receptor phosphorylation can be crucial, not only for initiation of G protein signaling but also in desensitization, internalization, downregulation, and cross-talk with other receptors.…”

Section: Marcil Et Al Identification Of a Novel C5l2 Variantmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a Novel C5L2 Variant (S323I) in a French Canadian Family With Familial Combined Hyperlipemia

Marcil

Vu²,

Cui³

et al. 2006

ATVB

View full text Add to dashboard Cite

Objective-A functional acylation stimulating protein (ASP) receptor, C5L2, has been recently identified in ASPresponsive cells. Impaired ASP-mediated triglyceride synthesis has previously been described in a subset of hyperapolipoprotein B/familial combined hyperlipidemia subjects. Methods and Results-DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G9683 T) in 1 subject, resulting in Ser3233 Ile substitution in the carboxyl terminal region. This variant was not detected in 2176 additional chromosomes by restriction fragment length polymorphism or fluorescence polarization genotyping. Eight family members of the proband were identified with one altered (ϩ/Ϫ)C5L2 allele. Nine other family members had the wild-type (ϩ/ϩ)C5L2 sequence. The abnormal allele was associated with increased plasma triglyceride, plasma cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and ASP. Of 23 subjects tested in cell-based ASP bioactivity assays, those with C5L2(ϩ/Ϫ) variant (nϭ2) had a 50% reduction in ASP-stimulated triglyceride synthesis, glucose transport and marked reduction in maximal binding (B max ). By contrast, a C5L2(ϩ/ϩ) family member responded normally, as did hyperapolipoprotein B normal ASP subjects compared with C5L2(ϩ/ϩ) controls (nϭ6). Key Words: acylation stimulating protein Ⅲ adipose Ⅲ C3adesArg Ⅲ gene defect Ⅲ G protein-coupled receptor Ⅲ hyperapolipoprotein B Ⅲ triglyceride synthesis I ncreased plasma apolipoprotein B (apoB) is a common dyslipoproteinemia associated with coronary artery disease 1 and is an excellent marker for diagnosis and treatment monitoring. 2 The hallmark is increased low-density lipoprotein (LDL) particles with overproduction of hepatic apoB 3 and increased small dense LDL particles. 4 Within this group, familial combined hyperlipidemia is considered to be the most frequent lipoprotein disorder in premature coronary artery disease (CAD). 5 The lipoprotein pattern varies in time and the level of penetrance may be incomplete, especially in premenopausal women. The pathogenesis of familial combined hyperlipidemia is complex and is very similar to that encountered in the metabolic syndrome. 6 This has hampered research in the cause of the disorder. Studies from Genest et al 7 and Castro-Cabezas et al 8 showed that hyperapolipoprotein B (hyperapoB) subjects have delayed triglyceride (TG) clearance and increased fatty acid after an oral fat load. 9 Peripheral resistance to fatty acid uptake in adipose tissue leads to increased hepatic flux, stimulating lipoprotein production. 10 We have proposed that, in a subset of patients, a defect in adipose tissue storage (particularly postprandially) might contribute to these abnormalities. Conclusion-TheIn support of this hypothesis, acylation stimulating protein (ASP) is a potential candidate. ASP binds to adipocytes and preadipocytes, promotes triglyceride synthesis through stimulation of both glucose transport and fatty acid esterification, 11,12 indirectly enhancing the action ...

show abstract

“…There are a limited number of common autoimmune disorders, and some diseases, such as type 1A diabetes (immune-mediated type 1 diabetes), both are common and have increased dramatically in incidence over the past 50 years (1). Irun Cohen has advanced the hypothesis that the normal immune repertoire includes a high frequency of lymphocytes that recognize key self-antigens.…”

Section: An Immunologic Homunculus For Type 1 Diabetesmentioning

confidence: 99%

Receptor heterodimerization: a new level of cross-talk

Barnes¹

2006

Journal of Clinical Investigation

View full text Add to dashboard Cite

Most G protein-coupled receptors (GPCRs) probably exist as homodimers, but it is increasingly recognized that GPCRs may also dimerize with other types of GPCRs and that this physical interaction may affect the function of either receptor. A study in this issue of the JCI demonstrates how heterodimerization between prostaglandin E receptors and β 2 -adrenergic receptors (β 2 ARs) in airway smooth muscle cells results in uncoupling of β 2 ARs and a diminished bronchodilator response to β 2 AR agonists (see the related article beginning on page 1400). This illustrates what we believe to be a novel mechanism of receptor cross-talk and highlights the potential importance of GPCR heterodimerization in diseases such as asthma and how this could lead to the development of more specific therapies in the future.

show abstract

G protein-coupled receptor cross-talk: pivotal roles of protein phosphorylation and protein?protein interactions

Cited by 80 publications

References 79 publications

Widespread CXCR4 Activation in Astrocytomas Revealed by Phospho-CXCR4-Specific Antibodies

Widespread CXCR4 Activation in Astrocytomas Revealed by Phospho-CXCR4-Specific Antibodies

Identification of a Novel C5L2 Variant (S323I) in a French Canadian Family With Familial Combined Hyperlipemia

Receptor heterodimerization: a new level of cross-talk

Contact Info

Product

Resources

About