Characterization of a postreceptor signaling defect that impairs cfos expression in cultured fibroblasts of a patient with insulin resistance

Induction of cfos expression is a definite end point of signal transduction by receptor tyrosine kinases via MAPK cascades, We have examined signal tr ansduction to transcription factor cFos in isolated fibroblasts of a patien t with an inherited syndrome of insulin resistance. MAPK phosphorylation an d activity were unaltered, but inducibility of cfos transcription was stron gly impaired by insulin and reduced by PDGF. Induction of the cfos promoter via MAPK is mediated by activation of the ternary complex. Abundance of SR F or Elk-1 was unaltered, but Elk-1 phosphorylation following stimulation w as reduced. Transient transfections with reporter genes under control of th e Elk-1 binding ets/sre cis element or expression plasmids coding for the r egulatory domain of Elk-1 fused to heterologous DNA binding domains reveale d a defect of Elk-1 activation in the patient cells. These data identify a novel postreceptor defect of insulin and growth factors involving activatio n of transcription. (C) 2000 Academic Press.