Cannabinoid Receptor-induced Neurite Outgrowth Is Mediated by Rap1 Activation through Gαo/i-triggered Proteasomal Degradation of Rap1GAPII

Jordan, J. Dedrick; He, John Cijiang; Eungdamrong, Narat J.; Gomes, Ivone; Ali, Wasif; Nguyen, Tracy; Bivona, Trever G.; Philips, Mark R.; Devi, Lakshmi A.; Iyengar, Ravi

doi:10.1074/jbc.m411521200

Cited by 116 publications

(108 citation statements)

References 23 publications

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“…Overexpression of Goα promotes neuritogenesis in several neuroblastoma cell lines, including PC12, N1E115 and Neuro2a cells [40,41]. In particular, previous studies by our group demonstrate that Goα regulates PKA signaling and increases the number of newly formed neurites [3,4], supporting its role as an activator of neuronal differentiation.…”

Section: Discussionsupporting

confidence: 58%

The alpha subunit of Go interacts with promyelocytic leukemia zinc finger protein and modulates its functions

Won¹,

Park²,

Ju³

et al. 2008

Cellular Signalling

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Section: Discussionsupporting

confidence: 58%

The alpha subunit of Go interacts with promyelocytic leukemia zinc finger protein and modulates its functions

Won¹,

Park²,

Ju³

et al. 2008

Cellular Signalling

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“…The consistency of increased gelatinase activity by the addition of PTX to controls in the present study suggests either an inhibitory Gi mediated pathway at baseline leading to decreased MMP-2 expression and/or activation in EOC cells (figure 6), or a Gi mediated proteosomal degradation. Jordan et al recently described a Gi coupled cannabionoid receptor pathway in Neuro-2A cells that target its interactor protein Rap1GAPII to proteasomal degradation, which was inversed by PTX [32]. One possible explanation of increased MMP2 activity in conditioned media of PTX-treated EOC cells is a similar Gi mediated targeting of the molecule for proteosomal degradation.…”

Section: Discussionmentioning

confidence: 99%

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Devine

Smicun

Hope

et al. 2008

Gynecologic Oncology

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OBJECTIVES-We previously demonstrated that sphingosine 1-phosphate (S1P) bimodally regulates epithelial ovarian cancer (EOC) cell invasiveness: low-concentration S1P stimulates invasion similar to lysophophatidic acid (LPA), while high-concentration S1P inhibits invasion. In this study, we investigated the mechanisms through which S1P affects EOC cell proteolysis, invasion, and adhesion in two cultured epithelial ovarian cancer cell lines. METHODS-G-proteinGi was inhibited by pertussis toxin (PTX) and GTP binding protein Rac by NSC23766. S1P conditioned media of DOV13 and OVCA429 cells were evaluated via gel zymography, fluorometric gelatinase assay, urokinase plasminogen activator (uPA) activity assay, and Western Blot for MT1-MMP. Cell invasion was analyzed in Matrigel chambers. Membrane-N-cadherin was localized via fluorescence microscopy.RESULTS-Zymography revealed pro-MMP2 in conditioned media of EOC cells regardless of treatment. Gelatinase activity was increased by low-concentration S1P. In DOV13 cells this effect was Gi and Rac dependent. In all OVCA429 and control DOV13 cells, PTX enhanced gelatinolysis, suggesting an MMP2-inhibitory pathway via Gi. MT1-MMP was decreased Gidependently by high-concentration S1P. Rac inhibition significantly counteracted low-S1P enhancement and high-S1P reduction of DOV13 invasiveness; and uPA activity in conditioned media of invading cells correlated significantly. Immunohistochemistry revealed Gi-dependent clustering of membrane-N-cadherin in DOV13 cells treated with 0.5µM S1P or 10µM LPA.CONCLUSIONS-S1P influences EOC invasion by regulating ECM-proteolysis and cell-cell attachment via MMP2, uPA, and membrane-N-cadherin. Furthermore, this study illustrates that the net effect of S1P on each of these processes reflects a complex interplay of multiple GPCR pathways involving Gi and downstream Rac.

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“…In this study, we characterize the interactions between Gα o/i and RGS20. Like the other Gα o/i interacting protein Rap1GAPII [10], we find that Gα o/i subunits stimulate the ubiquitination and proteasomal degradation of RGS20. This change in the level of RGS20 allows for differential interactions between the G s and G i pathways such that prior stimulation of the G i pathway leads to subsequent enhancement of inhibition of G s -stimulated cellular cAMP levels by concurrent stimulation of the G i pathway.…”

Section: Introductionmentioning

confidence: 64%

“…The decrease in levels of RGS20 upon co-expression with activated Gα o/i subunits was very reminiscent of the effect of Gα o co-expression with Rap1GAPII [10]. In the case of Rap1GAPII we had found Gα o stimulated ubiquitination and proteasomal degradation of Rap1GAPII.…”

Section: Resultsmentioning

confidence: 84%

“…More recently, we have sought to discover regulatory mechanisms whereby prior stimulation of the G i pathway affected stimulation of the G s pathway. We had found initial clues for such mechanism when we discovered that activated Gα o/i interacted with RGS20 in a yeast two-hybrid screen designed to identify direct interactors of Gα o [9,10]. RGS20, a member of the large family of GTPase activating proteins for the G i , G q and G 12/13 members of Gα subunits, was initially identified as a selective GAP for Gα z [11,12], although subsequently it has been shown that it has GAP activity towards other members of the G i family [13].…”

Section: Introductionmentioning

confidence: 99%

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Gαo/i-stimulated proteosomal degradation of RGS20: A mechanism for temporal integration of Gs and Gi pathways

Pagano

Jordan

Neves

et al. 2008

Cellular Signalling

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The G s and G i pathways interact to control the levels of intracellular cAMP. Although coincident signaling through G s and G i -coupled receptors can attenuate G s -stimulated cAMP levels, it is not known if prior activation of the G i pathway can affect signaling by G s -coupled receptors. We have found that activated Gα o/i interact with RGS20, a GTPase activating protein for members of the Gα o/i family. Interaction between Gα o/i and RGS20 results in decreased cellular levels of RGS20. This decrease was induced by activated Gα o and Gα i2 but not by Gα q , Gα i1 or Gα i3. The Gα o/iinduced decrease in RGS20 can be blocked by proteasomal inhibitors lactacystin or MG132. Activated Gα o stimulates the ubiquitination of RGS20. The serotonin-1A receptor that couples to G o/i reduces the levels of RGS20 and this effect is blocked by lactacystin, suggesting that G o/i promotes the degradation of RGS20. Expression of RGS20 attenuates the inhibition of β-adrenergic receptor-induced cAMP levels mediated by the serotonin-1A receptor. Prior activation of the serotonin-1A receptor results in loss of the RGS20-mediated attenuation, and the loss of attenuation is blocked when lactacystin is included during the prior treatment. These observations suggest that G o/i -coupled receptors, by stimulating the degradation of RGS20, can regulate how subsequent activation of the G s and G i pathways controls cellular cAMP levels, thus allowing for signal integration.

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Cannabinoid Receptor-induced Neurite Outgrowth Is Mediated by Rap1 Activation through Gαo/i-triggered Proteasomal Degradation of Rap1GAPII

Cited by 116 publications

References 23 publications

The alpha subunit of Go interacts with promyelocytic leukemia zinc finger protein and modulates its functions

The alpha subunit of Go interacts with promyelocytic leukemia zinc finger protein and modulates its functions

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Gαo/i-stimulated proteosomal degradation of RGS20: A mechanism for temporal integration of Gs and Gi pathways

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