title: Nongenomic estrogen action regulates tyrosine phosphatase activity and tuberin stability.
abstract: Estrogen action and tuberin function has been suggested to play a crucial role in the proliferation of lung smooth muscle-like cells and/or myofibroblasts in pulmonary lymphangioleiomyomatosis (LAM). Tuberin is a tumor suppressor phosphoprotein, which also regulates fluid phase endocytosis. Its activity, turnover and complex association with hamartin depends on its phosphorylation status. We have recently reported that nongenomic estrogen action regulates the phosphorylation status of several cytoplasmic proteins. Herein, we demonstrate that estrogen increases tyrosine phosphatase activity, which can be abrogated by antiestrogen ICI 182780 and tyrosine phosphatase inhibitor bpV(phen), but not by the protein synthesis inhibitor cyclohexamide. Furthermore, we show that estrogen transiently enhances the turnover of tuberin, which follows an inverse pattern to that observed for tyrosine phosphatase and endocytosis activity. We showed that tuberin phosphorylation protects it from degradation and induces its accumulation in female human lung fibroblasts and myofibroblasts. Our results suggest that nongenomic estrogen action induces tyrosine phosphatase activity that regulates stability of tyrosine phosphorylated proteins, including tuberin, which may play a crucial role in cellular specific functions such as endocytosis.
authors.affiliation: Department of Surgery and the Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, University of Southern California, 4650, Sunset Blvd. MS#35, 90027, USA. floresde@email.usc.edu
authors.forename: Guillermo
authors.initials: G
authors.lastname: Flores-Delgado
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Anderson
authors.forename: David
authors.initials: D
authors.lastname: Warburton
mesh_terms: D002460:Cell Line; D003546:Cysteine Endopeptidases; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000166:cytology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D004967:Estrogens; D009097:Multienzyme Complexes; D012097:Repressor Proteins; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D017027:Protein Tyrosine Phosphatases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex