It has been demonstrated that proinsulin C-peptide possesses several biological activities and that its specific binding sites are present on the surface of cell membranes. However, the molecular and cellular mechanisms of C-peptide actions are poorly known. In the present study we examined the possible involvement of the mitogen-activated protein kinase (MAPK) pathway in C-peptide effects. C-peptide induced the phosphorylation of MAPK [p44 extracellular signal-regulated kinase 1 (ERK1) and p42 ERK2] in Swiss 3T3 and 3T3-F442A fibroblasts but not in 3T3-L1 fibroblasts and some other cell lines such as L6E9 muscle cells. In Swiss 3T3 cells, C-peptide-induced phosphorylation of MAPK was dependent on time and concentration, being maximal at 1min and at 1nM C-peptide and was accompanied by an increase in MAPK activity and MAPK kinase (MEK) phosphorylation. The MAPK phosphorylation by C-peptide was abolished by treatment with pertussis toxin (PTX) and also with a MEK inhibitor, PD 98059. In addition, MAPK phosphorylation was attenuated by treatment with a phosphoinositide 3-kinase (PI-3K) inhibitor, wortmannin, and with a protein kinase C (PKC) inhibitor, GF109203X, and by down-regulation of PKC by prolonged treatment with PMA. Similar effects of the inhibitors and PTX were found on the MAPK phosphorylation induced by neuropeptide Y. These results suggest that C-peptide activates MAPK through a putative Gi/Go-linked receptor for C-peptide and through PI-3K-dependent and PKC-dependent pathways.
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Research Article|
February 26 2001
Proinsulin C-peptide rapidly stimulates mitogen-activated protein kinases in Swiss 3T3 fibroblasts: requirement of protein kinase C, phosphoinositide 3-kinase and pertussis toxin-sensitive G-protein
Takanori KITAMURA;
Takanori KITAMURA
*Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Kazuhiro KIMURA;
Kazuhiro KIMURA
1
*Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
1To whom correspondence should be addressed (e-mail k-kimura@vetmed.hokudai.ac.jp).
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Bae Dong JUNG;
Bae Dong JUNG
*Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Kennedy MAKONDO;
Kennedy MAKONDO
*Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Shiki OKAMOTO;
Shiki OKAMOTO
*Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Xavier CAÑAS;
Xavier CAÑAS
*Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Naoki SAKANE;
Naoki SAKANE
†First Department of Internal Medicine, Kyoto Prefectual University of Medicine, Kyoto 602-8566, Japan
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Toshihide YOSHIDA;
Toshihide YOSHIDA
†First Department of Internal Medicine, Kyoto Prefectual University of Medicine, Kyoto 602-8566, Japan
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Masayuki SAITO
Masayuki SAITO
*Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan
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Publisher: Portland Press Ltd
Received:
August 16 2000
Revision Received:
January 02 2001
Accepted:
January 29 2001
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2001
2001
Biochem J (2001) 355 (1): 123–129.
Article history
Received:
August 16 2000
Revision Received:
January 02 2001
Accepted:
January 29 2001
Citation
Takanori KITAMURA, Kazuhiro KIMURA, Bae Dong JUNG, Kennedy MAKONDO, Shiki OKAMOTO, Xavier CAÑAS, Naoki SAKANE, Toshihide YOSHIDA, Masayuki SAITO; Proinsulin C-peptide rapidly stimulates mitogen-activated protein kinases in Swiss 3T3 fibroblasts: requirement of protein kinase C, phosphoinositide 3-kinase and pertussis toxin-sensitive G-protein. Biochem J 1 April 2001; 355 (1): 123–129. doi: https://doi.org/10.1042/bj3550123
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