Hyperosmotic Induction of the Mitogen-Activated Protein Kinase Phosphatase MKP-1 in H4IIE Rat Hepatoma Cells

1998 ◽  
Vol 351 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Freimut Schliess ◽  
Sabine Heinrich ◽  
Dieter Häussinger
Keyword(s):  
Protein Kinase ◽  
Hepatoma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Rat Hepatoma ◽  
Rat Hepatoma Cells

scholarly journals Osmotic regulation of insulin-induced mitogen-activated protein kinase phosphatase (MKP-1) expression in H4IIE rat hepatoma cells

2003 ◽  
Vol 371 (2) ◽  
pp. 609-619 ◽  
Author(s):  
Mohammad Reza LORNEJAD-SCHÄFER ◽  
Christine SCHÄFER ◽  
Dirk GRAF ◽  
Dieter HÄUSSINGER ◽  
Freimut SCHLIESS
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Map Kinase ◽  
Hepatoma Cells ◽  
Kinase Activation ◽  
P70s6 Kinase ◽  
Mitogen Activated Protein ◽  
Pkc Ζ ◽  
Rat Hepatoma ◽  
Rat Hepatoma Cells

A contribution of intracellular dehydration to insulin resistance has been established in human subjects and in different experimental systems. Here the effect of hyperosmolarity (405mosmol/l) on insulin-induced mitogen-activated protein (MAP) kinase phosphatase (MKP)-1 expression was studied in H4IIE rat hepatoma cells. Insulin induces robust MKP-1 expression which correlates with a vanadate-sensitive decay of extracellular-signal-regulated kinase (Erk-1/Erk-2) activity. Hyperosmolarity delays MKP-1 accumulation by insulin and this corresponds to impaired MKP-1 synthesis, whereas MKP-1 degradation remains unaffected by hyperosmolarity. Rapamycin, which inhibits signalling downstream from the mammalian target of rapamycin (mTOR) and a peptide inhibiting protein kinase C (PKC) ζ/λ abolish insulin-induced MKP-1 protein but not mRNA expression, suggesting the involvement of the p70 ribosomal S6 protein kinase (p70S6-kinase) and/or the eukaryotic initiation factor 4E-binding proteins (4E-BPs) as well as atypical PKCs in MKP-1 translation. Hyperosmolarity induces sustained suppression of p70S6-kinase and 4E-BP1 hyperphosphorylation by insulin, whereas insulin-induced tyrosine phosphorylation of the insulin receptor (IR) β subunit and the IR substrates IRS1 and IRS2, recruitment of the phosphoinositide 3-kinase (PI 3-kinase) regulatory subunit p85 to the receptor substrates as well as PI 3-kinase activation, and Ser-473 phosphorylation of protein kinase B and Thr-410/403 phosphorylation of PKC ζ/λ are largely unaffected under hyperosmotic conditions. The hyperosmotic impairment of both, MKP-1 expression and p70S6-kinase hyperphosphorylation by insulin is insensitive to K2CrO4, calyculin A and vanadate, and inhibition of the Erk-1/Erk-2 and p38 pathways. The suppression of MKP-1 may further contribute to insulin resistance under dehydrating conditions by allowing unbalanced MAP kinase activation.

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