RGSZ1 interacts with protein kinase C interacting protein PKCI-1 and modulates mu opioid receptor signaling

Ajit, Seena K.; Ramineni, Suneela; Edris, Wade; Hunt, Rachel A.; Hum, Wah-Tung; Hepler, John R.; Young, Kimberly A.

doi:10.1016/j.cellsig.2006.09.008

Cited by 58 publications

(66 citation statements)

References 36 publications

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“…There are a large number of known JNK targets that couple to each of the individual anchoring proteins that bind JNK and have a variety of downstream effects (Davis, 2000;Bogoyevitch and Kobe, 2006;Engström et al, 2010). Alternatively, there are numerous regulatory proteins that are known to sequester or inactivate G-proteins, a number of which have been identified as regulating morphine signaling in the -opioid receptor system, in some cases in a protein kinase C-dependent manner (Garzón et al, 2005a,b;Rodríguez-Muñ oz et al, 2006;Ajit et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

et al. 2011

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The -opioid receptor is a widely expressed G-protein-coupled receptor that has been implicated in biological responses to pain, stress, anxiety, and depression, and its potential as a therapeutic target in these syndromes is becoming increasingly apparent. However, the prototypical selective -opioid antagonists have very long durations of action that have been attributed to c-Jun N-terminal kinase (JNK) 1 activation in vivo. To test generality of this proposed noncompetitive mechanism, we used C57BL/6 wild type mice to determine the durations of antagonist action of novel -opioid receptor ligands and examined their efficacies for JNK1 activation compared with conventional competitive antagonists. Of the 12 compounds tested, 5 had long durations of action that positively correlated with JNK activation: , and naloxone. After long-acting antagonist treatment, pJNK-ir did not increase in mice lacking the -opioid receptor; increased pJNK-ir returned to baseline by 48 h after treatment; and a second challenge with nor-BNI 72 h after the first did not increase pJNK-ir. Long-lasting antagonism and increased phospho-JNK-ir were not seen in animals lacking the JNK1 isoform. These results support the hypothesis that the duration of action of small molecule -opioid receptor antagonists in vivo is determined by their efficacy in activating JNK1 and that persistent inactivation of the -receptor does not require sustained JNK activation.

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Section: Discussionmentioning

confidence: 99%

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

et al. 2011

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“…The immune complexes or total cell lysates were probed for G␣i3 by Western blotting. interacting protein (PKCI-1) and modulates -opioid receptor signaling independent of RGSZ1-G␣z interaction (Ajit et al, 2007). RGS2 inhibits adenylyl cyclase activity (Sinnarajah et al, 2001) through its N terminus, also in an RGS domainindependent manner ( (Salim et al, 2003;Roy et al, 2006;Gu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Smad-Mediated Gene Transcription by RGS3

et al. 2008

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Regulator of G protein signaling (RGS) proteins are united into a family by the presence of the homologous RGS domain that binds the ␣ subunits of heterotrimeric G proteins and accelerates their GTPase activity. A member of this family, RGS3 regulates the signaling mediated by G q and G i proteins by binding the corresponding G␣ subunits. Here we show that RGS3 interacts with the novel partners Smad2, Smad3, and Smad4 -the transcription factors that are activated through a transforming growth factor-␤ (TGF-␤) receptor signaling. This interaction is mediated by the region of RGS3 outside of the RGS domain and by Smad's Mad homology 2 domain. Overexpression of RGS3 results in inhibition of Smad-mediated gene transcription. RGS3 does not affect TGF-␤-induced Smad phosphorylation, but it prevents heteromerization of Smad3 with Smad4, which is required for transcriptional activity of Smads. This translates to functional inhibition of TGF-␤-induced myofibroblast differentiation by RGS3. In conclusion, this study identifies a novel, noncanonical role of RGS3 in regulation of TGF-␤ signaling through its interaction with Smads and interfering with Smad heteromerization.

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“…Notably, the pCys string is perfectly conserved between RGS20 and 17, though RGS20 harbors a 31 residue N-terminal extension that RGS17 lacks. A significant body of evidence exists relating RGS20 function to the regulation of opioid signaling through the μ-opioid receptor (μOR) (25)(26)(27). As noted above, Ret-RGS is a splice variant of the gene that also encodes for RGS20, resulting Ret-RGS being 147 residues longer than RGS20.…”

Section: The Rz Familymentioning

confidence: 99%

“…Adopted from PDB Structures: 1AGR (Gα, RGS), 3SN6 (GPCR, Gα, βγ) (11,73) The most well-established noncanonical function of RGS17 is its ability to act as a scaffold in a complex surrounding the μOR. RGS17, as well as RGS19 and 20, interacts with histidine triad nucleotide binding protein 1(HINT1) through its pCys string, as first identified via Y2H screening for proteins that directly bind to RGS20 (25). The formation of this complex is dependent on the presence of Zn 2+ .…”

Section: Noncanonical Functions and Interactionsmentioning

confidence: 99%

Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers

Hayes

Roman

2016

AAPS J

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Abstract. Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling networks by terminating signals produced by active Gα subunits. RGS17, a member of the RZ subfamily of RGS proteins, is typically only expressed in appreciable amounts in the human central nervous system, but previous works have shown that RGS17 expression is selectively upregulated in a number of malignancies, including lung, breast, prostate, and hepatocellular carcinoma. In addition, this upregulation of RGS17 is associated with a more aggressive cancer phenotype, as increased proliferation, migration, and invasion are observed. Conversely, decreased RGS17 expression diminishes the response of ovarian cancer cells to agents commonly used during chemotherapy. These somewhat contradictory roles of RGS17 in cancer highlight the need for selective, high-affinity inhibitors of RGS17 to use as chemical probes to further the understanding of RGS17 biology. Based on current evidence, these compounds could potentially have clinical utility as novel chemotherapeutics in the treatment of lung, prostate, breast, and liver cancers. Recent advances in screening technologies to identify potential inhibitors coupled with increasing knowledge of the structural requirements of RGS-Gα protein-protein interaction inhibitors make the future of drug discovery efforts targeting RGS17 promising. This review highlights recent findings related to RGS17 as both a canonical and atypical RGS protein, its role in various human disease states, and offers insights on small molecule inhibition of RGS17.

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RGSZ1 interacts with protein kinase C interacting protein PKCI-1 and modulates mu opioid receptor signaling

Cited by 58 publications

References 36 publications

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

Duration of Action of a Broad Range of Selective κ-Opioid Receptor Antagonists Is Positively Correlated with c-Jun N-Terminal Kinase-1 Activation

Regulation of Smad-Mediated Gene Transcription by RGS3

Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers

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