An S6 kinase activated during liver regeneration is related to the insulin-stimulated S6 kinase in H4 hepatoma cells.
Protein kinase activity toward the 40 S ribosomal protein S6 is activated 6-fold in regenerating rat liver following 70% hepatectomy. The kinase is maximally activated within 2 h after surgery, remains active up to 36 h after surgery, and declines rapidly thereafter. The post-hepatectomy S6 kinase activity exhibits structural and functional similarity to an insulin-stimulated S6 kinase in H4 hepatoma cells. Both S6 kinase activities are cAMP- and Ca2+-independent, and have a requirement for [ethylenebis(oxyethylenenitrilo)]tetraacetic acid. The regenerating liver and the insulin-stimulated H4 hepatoma S6 kinase elute at similar positions when sequentially fractionated by anion-exchange and cation-exchange chromatography. Both enzymes migrate at Mr 70,000 on fast protein liquid chromatography Superose 12 gel filtration. In H4 hepatoma cells, activation of S6 kinase activity is reversed by removal of insulin, and the cells can then be restimulated. Freshly isolated hepatocytes from normal animals show low levels of S6 kinase activity which can be stimulated by epidermal growth factor and insulin. Hepatocytes prepared from regenerating liver remnant have constitutively high levels of S6 kinase activity, which is unresponsive to insulin plus epidermal growth factor and which remains elevated at least 2 h in the absence of exogenously added growth factors. These findings demonstrate S6 protein kinase activation in vivo, in the setting of regulated cell growth; as in cultured cells, activation of S6 kinase probably represents an early step in the pleiotypic response elicited by activation of growth factor receptors.
Nemenoff
R A
RA
Howard Hughes Medical Institute Laboratories, Harvard Medical School, Massachusetts General Hospital, Boston.
Price
D J
DJ
Mendelsohn
M J
MJ
Carter
E A
EA
Avruch
J
J
D000818:Animals; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D006498:Hepatectomy; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D008115:Liver Regeneration; D008297:Male; D006656:Protamine Kinase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins / Q000378:metabolism*; D013997:Time Factors
D007328:Insulin; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D004815:Epidermal Growth Factor; D005934:Glucagon; D011494:Protein Kinases; D006656:Protamine Kinase