G protein coupled receptor transactivation: Extending the paradigm to include serine/threonine kinase receptors

Burch, Micah L; Osman, Narin; Getachew, Robel; Al-aryahi, Sefaa; Poronnik, Philip; Zheng, Wenhua; Hill, Michael A.; Little, Peter J.

doi:10.1016/j.biocel.2012.01.018

Cited by 31 publications

(31 citation statements)

References 46 publications

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“…On the basis of these results, we hypothesized an involvement of the TGF-βRI in the chemoresistant cells response to 5FU. In order to verify if the LiCl-mediated TGF-βRI downregulation was an off-target effect or a specific molecular regulation involved in chemoresistance, we inhibited the TGF-βRI by using SB431542, a well-known inhibitor of this serine/threonine kinase receptor [12, 25, 26]. Proliferation analysis showed that SB431542 treatment was able to dramatically decrease Ki67 expression in combination with 5FU, in HCT116p53KO cells (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

“…No previous literature reports LiCl-mediated TGF-βRI downregulation. In order to exclude a LiCl off-target effect on TGF-βRI, we specifically inhibited TGF-βRI by using SB431542, a well-known TGF-βRI inhibitor [12, 25, 26]. We observed that TGF-βRI specific inhibition in combination with 5FU was able to re-sensitize chemoresistant cells to chemotherapeutic action, in terms of inhibition of proliferation (Figure 3) and induction of cell death (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

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The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells

et al. 2016

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TGF-β pathway is generally associated with the processes of metastasis, angiogenesis and EMT in cancer. Very little is known, however, about the role of TGF-β in cancer drug resistance. In this work, we show a specific activation of the TGF-β pathway in consequence of chemotherapeutic treatment in in vivo and in vitro models of colorectal carcinoma. 5-Fluorouracil (5FU) was able to stimulate the activation of SMAD3 and the transcription of specific genes such as ACVRL1, FN1 and TGFB1. On the other hand, the specific inhibition of TGF-βRI was able to repress the 5FU-induced genes transcription and to restore the sensitivity of chemoresistant cells to the toxic action of the drug, by decreasing the expression of BCL2L1 and ID1 genes. The role of the TGF-β molecule in the chemoresistant colon carcinoma cells' response to 5FU was further demonstrated by conditioned medium (CM) experiments: CM from 5FU-treated chemoresistant cells was able to protect chemosensitive cells against the toxic action of 5FU. In conclusion, these findings showed the pivotal role of TGF-β pathway in colon cancer mechanisms of drug resistance suggesting new possible approaches in diagnosis and treatment of colon cancer patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells

et al. 2016

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“…Specifically, the GPCR agonists endothelin-1 and thrombin can induce phosphorylation of Smad2, which is directly downstream of the TGFβ receptor. This Smad2 phosphorylation is inhibited by treatment with endothelin receptor and PAR1 antagonists (24, 59, 60). Recently, our lab has reported that MMP-mediated receptor transactivation can also lead to biased agonism at the transactivated receptor, PAR1.…”

Section: Signal Transduction Downstream Of Extracellular Protease-medmentioning

confidence: 99%

G Protein Coupled Receptor-mediated Transactivation of Extracellular Proteases

Schafer

Blaxall

2017

Journal of Cardiovascular Pharmacology

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G protein-coupled receptors (GPCRs) comprise the largest family of receptors in humans. Traditional activation of GPCRs involves binding of a ligand to the receptor, activation of heterotrimeric G proteins and induction of subsequent signaling molecules. It is now known that GPCR signaling occurs through G protein-independent pathways including signaling through β-arrestin as well as transactivation of other receptor types. Generally, transactivation occurs when activation of one receptor leads to the activation of another receptor(s). GPCR-mediated transactivation is an essential component of GPCR signaling, as activation of other receptor types, such as receptor tyrosine kinases (RTKs), allows GPCRs to expand their signal transduction and affect various cellular responses. Several mechanisms have been identified for receptor transactivation downstream of GPCRs, one of which involves activation of extracellular proteases, such as A Disintegrin and Metalloprotease (ADAMs) and matrix metalloproteases (MMPs). These proteases cleave and release ligands that are then able to activate their respective receptors. ADAMs and MMPs can be activated via various mechanisms downstream of GPCR activation, including activation via second messenger, direct phosphorylation or direct G protein interaction. Additional understanding of the mechanisms involved in GPCR-mediated protease activation and subsequent receptor transactivation could lead to identification of new therapeutic targets.

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“…Some GPCRs can activate serine/ threonine kinase receptors specifically from the TGF-b receptor super family [34,38,67,68] (see Table 1). …”

Section: Gpcr Transactivation Of Serine/threonine Kinase Receptorsmentioning

confidence: 99%

The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

Kamato

Rostam

Bernard

et al. 2014

Cell. Mol. Life Sci.

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G protein-coupled receptor (GPCR) signalling is mediated through transactivation-independent signalling pathways or the transactivation of protein tyrosine kinase receptors and the recently reported activation of the serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Since the original observation of GPCR transactivation of protein tyrosine kinase receptors, there has been considerable work on the mechanism of transactivation and several pathways are prominent. These pathways include the "triple membrane bypass" pathway and the generation of reactive oxygen species. The recent recognition of GPCR transactivation of serine/threonine kinase receptors enormously broadens the GPCR signalling paradigm. It may be predicted that the transactivation of serine/threonine kinase receptors would have mechanistic similarities with transactivation of tyrosine kinase pathways; however, initial studies suggest that these two transactivation pathways are mechanistically distinct. Important questions are the relative importance of tyrosine and serine/threonine transactivation pathways, the contribution of transactivation to overall GPCR signalling, mechanisms of transactivation and the range of cell types in which this phenomenon occurs. The ultimate significance of transactivation-dependent signalling remains to be defined but it appears to be prominent and if so will represent a new cell signalling frontier.

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G protein coupled receptor transactivation: Extending the paradigm to include serine/threonine kinase receptors

Cited by 31 publications

References 46 publications

The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells

The TGF-β pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells

G Protein Coupled Receptor-mediated Transactivation of Extracellular Proteases

The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

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