Proinsulin C-peptide activates CRE binding proteins through the p38 MAP kinase pathway in mouse lung capillary endothelial cell
Takanori Kitamura et al
Biochemical Journal Immediate Publication
Proinsulin C-peptide has been reported to have some biological activities and to bepossibly involved in the development of diabetic microangiopathy. In the presentstudy, we examined the effects of C-peptide on the mitogen-activated protein kinasepathway in LEII mouse lung capillary endothelial cells. Stimulation of the cells withC-peptide increased both p38 stress-activated protein kinase (p38MAPK) andextracellular signal-regulated kinases (ERK1/2) activities and activity-related site-specific phosphorylation of the respective kinases in a concentration dependent manner,but failed to activate c-Jun amino-terminal kinase. Stimulation of the cells with C-peptide also induced site-specific phosphorylation of cyclic AMP responsive elementbinding protein (CREB)/activating transcription factor 1(ATF1), and thereby binding ofthese transcription factors to CRE. Among three CREB kinases tested,phosphorylation of MAPK-activated protein kinase 2 (MAPKAP-K2) was induced afterstimulation with C-peptide. The phosphorylation of CREB, ATF1 and MAPKAP-K2were inhibited by SB203580, a p38MAPK inhibitor, but not by PD98059, an ERKkinase inhibitor. These results indicate that C-peptide activates p38MAPK followedby MAPKAP-K2 to enhance DNA-CREB/ATF1 interaction.