Evidence that guanine-nucleotide binding regulatory proteins couple cell-surface receptors to the breakdown of inositol-containing lipids during T-lymphocyte mitogenesis.
We have studied the role of guanine-nucleotide binding regulatory proteins (G proteins) in the stimulation of inositol lipid breakdown during mitogenic activation of normal human T lymphocytes. The effect of the mitogen phytohemagglutinin (PHA) was compared with the action of two G-protein activators, fluoroaluminate (AlF4-) and guanosine-5'-O-thiotriphosphate (GTP gamma S). PHA and AlF4- stimulated the breakdown of inositol lipids via both the phospholipase A and C pathways when added to intact lymphocytes. PHA, AlF4- and GTP gamma S also triggered both these pathways when added to permeable lymphocytes. The magnitude of the response obtained with AlF4- and GTP gamma S was about four-fold less than with PHA. This difference was attributable to increases in cAMP elicited by AlF4- and GTP gamma S which inhibited the phospholipase pathways. AlF4-, GTP gamma S, and PHA all stimulated the phosphorylation of a 42 kDa protein on tyrosine residues. We propose a model for the early steps following mitogen binding, including sequential activation of a G protein, phospholipase C, protein kinase C and a tyrosine protein kinase. A parallel pathway involving G protein mediated activation of phospholipase A is also implicated.
D000535:Aluminum / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D005461:Fluorine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000502:physiology*; D010716:Phosphatidylinositols / Q000502:physiology*; D010741:Phospholipases A / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D010716:Phosphatidylinositols; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D013873:Thionucleotides; C053629:fluoroaluminum; D019000:Phosphotyrosine; D005461:Fluorine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D014443:Tyrosine; D006160:Guanosine Triphosphate; D000535:Aluminum; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D010741:Phospholipases A; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins