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Betagamma subunits of G(i/o) suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced.
Cell Signal. 2008 Jul; 20(7):1275-83.CS

Abstract

Extracellular signal-regulated kinases (ERKs) play important physiological roles in proliferation, differentiation and gene expression. ERK5 is twice the size of ERK1/2, the amino-terminal half contains the kinase domain that shares the homology with ERK1/2 and TEY activation motif, whereas the carboxy-terminal half is unique. In this study, we examined the cross-talk mechanism between G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases, focusing on ERK1/2 and 5. The pretreatment of rat pheochromocytoma cells (PC12) with pertussis toxin (PTX) specifically enhanced epidermal growth factor (EGF)-induced ERK5 phosphorylation. In addition, lysophosphatidic acid (LPA) attenuated the EGF-induced ERK5 phosphorylation in LPA(1) receptor- and G(i/o)-dependent manners. On the other hand, LPA alone activated ERK1/2 via Gbetagamma subunits and Ras and potentiated EGF-induced ERK1/2 phosphorylation at late time points. These results suggest G(i/o) negatively regulates ERK5, while it positively regulates ERK1/2. LPA did not affect cAMP levels after EGF treatment, and the reagents promoting cAMP production such as forskolin and cholera toxin also attenuated the EGF-induced ERK5 phosphorylation, indicating that the inhibitory effect of LPA on ERK5 inhibition via G(i/o) is not due to inhibition of adenylyl cyclase by Galpha(i/o). However, the inhibitory effect of LPA on ERK5 was abolished in PC12 cells stably overexpressing C-terminus of GPCR kinase2 (GRK2), and overexpression of Gbeta(1) and gamma(2) subunits also suppressed ERK5 phosphorylation by EGF. In response to LPA, Gbetagamma subunits interacted with EGF receptor in a time-dependent manner. These results strongly suggest that LPA negatively regulates the EGF-induced ERK5 phosphorylation through Gbetagamma subunits.

Authors+Show Affiliations

Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan. obaray@mail.pharm.tohoku.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18407464

Citation

Obara, Yutaro, et al. "Betagamma Subunits of G(i/o) Suppress EGF-induced ERK5 Phosphorylation, Whereas ERK1/2 Phosphorylation Is Enhanced." Cellular Signalling, vol. 20, no. 7, 2008, pp. 1275-83.
Obara Y, Okano Y, Ono S, et al. Betagamma subunits of G(i/o) suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced. Cell Signal. 2008;20(7):1275-83.
Obara, Y., Okano, Y., Ono, S., Yamauchi, A., Hoshino, T., Kurose, H., & Nakahata, N. (2008). Betagamma subunits of G(i/o) suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced. Cellular Signalling, 20(7), 1275-83. https://doi.org/10.1016/j.cellsig.2008.02.016
Obara Y, et al. Betagamma Subunits of G(i/o) Suppress EGF-induced ERK5 Phosphorylation, Whereas ERK1/2 Phosphorylation Is Enhanced. Cell Signal. 2008;20(7):1275-83. PubMed PMID: 18407464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Betagamma subunits of G(i/o) suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced. AU - Obara,Yutaro, AU - Okano,Yumiko, AU - Ono,Sachiko, AU - Yamauchi,Arata, AU - Hoshino,Tomohiro, AU - Kurose,Hitoshi, AU - Nakahata,Norimichi, Y1 - 2008/03/04/ PY - 2007/12/18/received PY - 2008/02/22/revised PY - 2008/02/22/accepted PY - 2008/4/15/pubmed PY - 2008/9/3/medline PY - 2008/4/15/entrez SP - 1275 EP - 83 JF - Cellular signalling JO - Cell Signal VL - 20 IS - 7 N2 - Extracellular signal-regulated kinases (ERKs) play important physiological roles in proliferation, differentiation and gene expression. ERK5 is twice the size of ERK1/2, the amino-terminal half contains the kinase domain that shares the homology with ERK1/2 and TEY activation motif, whereas the carboxy-terminal half is unique. In this study, we examined the cross-talk mechanism between G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases, focusing on ERK1/2 and 5. The pretreatment of rat pheochromocytoma cells (PC12) with pertussis toxin (PTX) specifically enhanced epidermal growth factor (EGF)-induced ERK5 phosphorylation. In addition, lysophosphatidic acid (LPA) attenuated the EGF-induced ERK5 phosphorylation in LPA(1) receptor- and G(i/o)-dependent manners. On the other hand, LPA alone activated ERK1/2 via Gbetagamma subunits and Ras and potentiated EGF-induced ERK1/2 phosphorylation at late time points. These results suggest G(i/o) negatively regulates ERK5, while it positively regulates ERK1/2. LPA did not affect cAMP levels after EGF treatment, and the reagents promoting cAMP production such as forskolin and cholera toxin also attenuated the EGF-induced ERK5 phosphorylation, indicating that the inhibitory effect of LPA on ERK5 inhibition via G(i/o) is not due to inhibition of adenylyl cyclase by Galpha(i/o). However, the inhibitory effect of LPA on ERK5 was abolished in PC12 cells stably overexpressing C-terminus of GPCR kinase2 (GRK2), and overexpression of Gbeta(1) and gamma(2) subunits also suppressed ERK5 phosphorylation by EGF. In response to LPA, Gbetagamma subunits interacted with EGF receptor in a time-dependent manner. These results strongly suggest that LPA negatively regulates the EGF-induced ERK5 phosphorylation through Gbetagamma subunits. SN - 0898-6568 UR - https://www.unboundmedicine.com/medline/citation/18407464/Betagamma_subunits_of_G_i/o__suppress_EGF_induced_ERK5_phosphorylation_whereas_ERK1/2_phosphorylation_is_enhanced_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(08)00082-X DB - PRIME DP - Unbound Medicine ER -