βγ subunits of Gi/o suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced

Yutaro Obara, Yumiko Okano, Sachiko Ono, Arata Yamauchi, Tomohiro Hoshino, Hitoshi Kurose, Norimichi Nakahata

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 LPA1 receptor- and Gi/o-dependent manners. On the other hand, LPA alone activated ERK1/2 via Gβγ subunits and Ras and potentiated EGF-induced ERK1/2 phosphorylation at late time points. These results suggest Gi/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 Gi/o is not due to inhibition of adenylyl cyclase by Gαi/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 Gβ1 and γ2 subunits also suppressed ERK5 phosphorylation by EGF. In response to LPA, Gβγ subunits interacted with EGF receptor in a time-dependent manner. These results strongly suggest that LPA negatively regulates the EGF-induced ERK5 phosphorylation through Gβγ subunits.

Original languageEnglish
Pages (from-to)1275-1283
Number of pages9
JournalCellular Signalling
Volume20
Issue number7
DOIs
Publication statusPublished - Jul 1 2008

Fingerprint

Epidermal Growth Factor
Phosphorylation
PC12 Cells
G-Protein-Coupled Receptors
Lysophosphatidic Acid Receptors
Cholera Toxin
Extracellular Signal-Regulated MAP Kinases
Pertussis Toxin
Receptor Protein-Tyrosine Kinases
Pheochromocytoma
Colforsin
lysophosphatidic acid
Epidermal Growth Factor Receptor
Adenylyl Cyclases
Phosphotransferases
Gene Expression

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

βγ subunits of Gi/o suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced. / Obara, Yutaro; Okano, Yumiko; Ono, Sachiko; Yamauchi, Arata; Hoshino, Tomohiro; Kurose, Hitoshi; Nakahata, Norimichi.

In: Cellular Signalling, Vol. 20, No. 7, 01.07.2008, p. 1275-1283.

Research output: Contribution to journalArticle

Obara, Yutaro ; Okano, Yumiko ; Ono, Sachiko ; Yamauchi, Arata ; Hoshino, Tomohiro ; Kurose, Hitoshi ; Nakahata, Norimichi. / βγ subunits of Gi/o suppress EGF-induced ERK5 phosphorylation, whereas ERK1/2 phosphorylation is enhanced. In: Cellular Signalling. 2008 ; Vol. 20, No. 7. pp. 1275-1283.
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