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Activation of ras-dependent signaling pathways by G14-coupled receptors requires the adaptor protein TPR1
Kwan D.H.T.1; Yung L.Y.1; Ye R.D.2; Wong Y.H.1
2012-11-01
Source PublicationJournal of Cellular Biochemistry
ISSN07302312 10974644
Volume113Issue:11Pages:3486-3497
AbstractMany G-coupled receptors mediate mitogenic signals by stimulating extracellular signal-regulated protein kinases (ERKs) that are typically regulated by the small GTPase Ras. Recent studies have revealed that members of the Gα family may possess the ability to activate Ras/ERK by interacting with the adaptor protein tetratricopeptide repeat 1 (TPR1). Within the Gα family, the highly promiscuous Gα can relay signals from numerous receptors. Here, we examined if Gα interacts with TPR1 to stimulate Ras signaling pathways. Expression of the constitutively active GαQL mutant in HEK293 cells led to the formation of GTP-bound Ras as well as increased phosphorylations of downstream signaling molecules including ERK and IκB kinase. Stimulation of endogenous G-coupled somatostatin type 2 and α-adrenergic receptors produced similar responses in human hepatocellular HepG2 carcinoma cells. Co-immunoprecipitation assays using HEK293 cells demonstrated a stronger association of TPR1 for GαQL than Gα, suggesting that TPR1 preferentially binds to the GTP-bound form of Gα. Activated Gα also interacted with the Ras guanine nucleotide exchange factors SOS1 and SOS2. Expression of a dominant negative mutant of TPR1 or siRNA-mediated knockdown of TPR1 effectively abolished the ability of Gα to induce Ras signaling in native HepG2 or transfected HEK293 cells. Although expression of the dominant negative mutant of TPR1 suppressed GαQL-induced phosphorylations of ERK and IκB kinase, it did not affect GαQL-induced stimulation of phospholipase Cβ or c-Jun N-terminal kinase. Our results suggest that TPR1 is required for Gα to stimulate Ras-dependent signaling pathways, but not for the propagation of signals along Ras-independent pathways. J. Cell. Biochem. 113: 3486-3497, 2012. © 2012 Wiley Periodicals, Inc.
KeywordERK Gα14 IKK PLCβ Ras TPR1
DOI10.1002/jcb.24225
URLView the original
Language英語
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Cited Times [WOS]:4   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Hong Kong University of Science and Technology
2.University of Illinois College of Medicine
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GB/T 7714
Kwan D.H.T.,Yung L.Y.,Ye R.D.,et al. Activation of ras-dependent signaling pathways by G14-coupled receptors requires the adaptor protein TPR1[J]. Journal of Cellular Biochemistry,2012,113(11):3486-3497.
APA Kwan D.H.T.,Yung L.Y.,Ye R.D.,&Wong Y.H..(2012).Activation of ras-dependent signaling pathways by G14-coupled receptors requires the adaptor protein TPR1.Journal of Cellular Biochemistry,113(11),3486-3497.
MLA Kwan D.H.T.,et al."Activation of ras-dependent signaling pathways by G14-coupled receptors requires the adaptor protein TPR1".Journal of Cellular Biochemistry 113.11(2012):3486-3497.
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