The signal peptide of the rat corticotropin-releasing factor receptor 1 promotes receptor expression but is not essential for establishing a functional receptor

Alken, Martina; Rutz, Claudia; Köchl, Robert; Donalies, Ute; Oueslati, Morad; Furkert, Jens; Wietfeld, Doreen; Hermosilla, Ricardo; Scholz, Anne; Beyermann, Michael; Rosenthal, Walter; Schülein, Ralf

doi:10.1042/bj20050113

Cited by 43 publications

(56 citation statements)

References 29 publications

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“…Antibodies-The polyclonal rabbit anti-GFP antiserum 01 (raised against a glutathione S-transferase-GFP fusion protein) have been described (14). The monoclonal mouse anti-GFP antibody was purchased from Clontech Laboratories.…”

Section: Methodsmentioning

confidence: 99%

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The Corticotropin-releasing Factor Receptor Type 2a Contains an N-terminal Pseudo Signal Peptide

Rutz

Renner

Alken

et al. 2006

Journal of Biological Chemistry

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The corticotropin-releasing factor (CRF) 3 receptor family is involved in the regulation of the hypothalamic-pituitary-adrenal stress axis in mammals (1-3). A large body of evidence points to a major role of the receptors in mediating CRF effects in anxiety and depressive disorders and in stress-associated pathologies. Two types of CRF receptors are known, the CRF 1 and the CRF 2 receptors. The CRF 1 receptor is expressed mainly in the pituitary and central nervous system and binds CRF with high affinity. It mediates adrenocorticotrophic hormone release from the anterior pituitary and is involved in the endocrine, autonomic, and cognitive responses to stress stimuli. The CRF 2 receptors are expressed in the central nervous system but also in the periphery including skeletal muscle cells, cardiac myocytes, and cells of the gastrointestinal tract. Three splice variants of CRF 2 receptors have been described: CRF 2(a) , CRF 2(b) , and CRF 2(c) receptors. They bind CRF with low and the urocortins 1-3 with high affinity. The CRF 2 receptors are involved in the regulation of feeding behavior (4) and in recovery from a stress response (5). It is likely that they are also involved in modulating anxiety-related behavior.The CRF receptors belong to the small subgroup of GPCRs (5-10%) possessing putative N-terminal signal peptides. These peptides are believed to be cleaved-off after mediating the ER targeting/insertion process (6, 7). The majority (90 -

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Section: Methodsmentioning

confidence: 99%

“…Signal peptides may also facilitate predominantly ER targeting. Such a function was recently described for the signal peptide of the CRF 1 receptor (14). Here, we have assessed the functional significance of the putative signal peptide of the CRF 2(a) receptor.…”

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confidence: 99%

The Corticotropin-releasing Factor Receptor Type 2a Contains an N-terminal Pseudo Signal Peptide

Rutz

Renner

Alken

et al. 2006

Journal of Biological Chemistry

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“…For GPCRs, signal peptides are usually rare, and only about 5-10 % of GPCRs are predicted to possess one. These are typically found in GPCRs which possess very long Ntermini involved in ligand binding, such as members of the glycoprotein hormone receptor family, as well as secretin and glutamate receptors [53,55,56]. Only very few class A GPCRs exhibit predicted signal peptides and their function is in most cases not well understood [53].…”

Section: Discussionmentioning

confidence: 99%

The rat adenine receptor: pharmacological characterization and mutagenesis studies to investigate its putative ligand binding site

Knospe

Müller

Rosa

et al. 2013

Purinergic Signalling

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The rat adenine receptor (rAdeR) was the first member of a family of G protein-coupled receptors (GPCRs) activated by adenine and designated as P0-purine receptors. The present study aimed at gaining insights into structural aspects of ligand binding and function of the rAdeR. We exchanged amino acid residues predicted to be involved in ligand binding (Phe110 3.24 47 , were found to be crucial for activation since their alanine mutants did not respond to adenine. Moreover we showed that-in contrast to most other rhodopsin-like GPCRs-the rAdeR does not contain essential disulfide bonds since preincubation with dithiothreitol neither altered adenine binding in Sf9 cell membranes, nor adenineinduced inhibition of adenylate cyclase in 1321N1 astrocytoma cells transfected with the rAdeR. To detect rAdeRs by Western blot analysis, we developed a specific antibody. Finally, we were able to show that the extended N-terminal sequence of the rAdeR constitutes a putative signal peptide of unknown function that is cleaved off in the mature receptor. Our results provide important insights into this new, poorly investigated family of purinergic receptors.

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“…The lysates were cleared by centrifugation (20,000 ϫ g, 4°C, 10 min). Proteins were immunoprecipitated with anti-GFP (62,63) or anti-GSK3␤ (L-17, Goat, Santa Cruz Biotechnology, Dallas, TX) antibodies, and protein A-conjugated agarose (Sigma-Aldrich) or anti-FLAG-coupled magnetic beads (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

Dema

Schröter

Perets

et al. 2016

Journal of Biological Chemistry

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The A-kinase anchoring protein (AKAP) GSK3␤ interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3␤ (GSK3␤). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3␤ are required for the regulation of ␤-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets ␤-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause ␤-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the ␤-catenin stabilizing phosphorylation at Ser-675 by PKA. Its interaction with GSK3␤ facilitates control of the destabilizing phosphorylation of ␤-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on ␤-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with ␤-catenin. The regulation of ␤-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3␤, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3␤ is a conserved GSK3␤ interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3␤ by GSKIP, and ascribe a function to a cytosolic AKAP-PKA interaction as a regulatory factor in the control of canonical Wnt signaling. Wnt signaling controls different biological processes, including embryonic development, cell cycle progression, glycogen metabolism, and immune regulation; deregulation is associated with diseases such as cancer, type 2 diabetes, inflammatory, and Alzheimer's and Parkinson's diseases.A-kinase anchoring proteins (AKAPs) 3 are a family of about 50 scaffolding proteins. Their conserved function is the compartmentalization of protein kinase A (PKA). PKA holoenzyme consists of a dimer of regulatory (RI␣, RI␤, RII␣, or RII␤) and two catalytic subunits each bound to one R subunit. AKAPs directly interact with R subunits and tether the kinase to defined cellular compartments such as vesicles, the sarcoplasmic reticulum, or the cytoskeleton. This compartmentalization confers a tight spatiotemporal control to PKA signaling, and enables PKA to elicit a specific cellular response to each of the many stimuli that cause cAMP elevation and thereby lead to activation of this ubiquitous kinase. AKAPs directly interact with further signaling proteins, thus mediating crosstalk between signaling systems: phosphatases, dephosphorylating PKA-phosphorylated substrates, adenylyl cyclases, synthesizing cAMP, and phosphodiesterases (PDEs), hydrolyzing cAMP. Several AKAPs bind further kinases such as protein kinase C (PKC), which are activated by signals other than cAMP, e.g. Ca 2ϩ . AKAPs and their interactions play key roles in a variety of physiological processes such as vasopressin-mediated water reabsorption in renal principal cells and cardiac myocyte contractility (1-5, 7, 8).A new example...

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The signal peptide of the rat corticotropin-releasing factor receptor 1 promotes receptor expression but is not essential for establishing a functional receptor

Cited by 43 publications

References 29 publications

The Corticotropin-releasing Factor Receptor Type 2a Contains an N-terminal Pseudo Signal Peptide

The Corticotropin-releasing Factor Receptor Type 2a Contains an N-terminal Pseudo Signal Peptide

The rat adenine receptor: pharmacological characterization and mutagenesis studies to investigate its putative ligand binding site

The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3β Interaction Protein (GSKIP) Regulates β-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3β

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