Morphogen-induced decline in Gialpha2 triggers F9 teratocarcinoma stem cell progression via phospholipase C and mitogen-activated protein kinase.
The linkage between Gialpha2 and morphogen-induced promotion of F9 embryonic teratocarcinoma stem (F9 stem) cells to primitive endoderm was explored using probes of the mitogen-activated protein (MAP) kinase network. The morphogen-induced decline in Gialpha2 is shown to trigger activation of phospholipase C, thereby activating protein kinase C, MAP kinase, and cell progression to primitive endoderm. In the absence of retinoic acid, reduction-of-function mutants (Gialpha2-deficient) display the effects of morphogen, i.e. activation of phospholipase C, protein kinase C, MAP kinase, and progression to primitive endoderm. Gain-of-function mutants (expressing the Q205L activating-mutation of Gialpha2) displayed no activation of phospholipase C, protein kinase C, MAP kinase and no progression to primitive endoderm, even in the presence of retinoic acid. Selective inhibitors of protein kinase C, like the gain-of-function mutations, effectively block morphogen-induced progression to primitive endoderm. Morphogen triggers F9 stem cell progression by triggering Gialpha2 loss and thereby activation of downstream elements, including protein kinase C and MAP kinase.
Gao
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Department of Molecular Pharmacology, Diabetes and Metabolic Diseases Research Program, University Medical Center-HSC, State University of New York, Stony Brook, New York 11794-8651, USA.
Malbon
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CC
D000818:Animals; D002118:Calcium / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D004075:Diglycerides / Q000378:metabolism; D054278:Embryonal Carcinoma Stem Cells; D004707:Endoderm / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011493:Protein Kinase C / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D018243:Teratocarcinoma / Q000473:pathology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000502:physiology*
D004075:Diglycerides; D012333:RNA, Messenger; D014212:Tretinoin; D011494:Protein Kinases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium