title: Engulfment protein GULP is regulator of transforming growth factor-β response in ovarian cells.
abstract: Transforming growth factor β (TGF-β) is a key regulatory molecule with pleiotropic effects on cell growth, migration, and invasion. As a result, impairment of proper TGF-β signaling is central to tumorigenesis and metastasis. The TGF-β receptor V (TGFBRV or LRP1) has been shown to be responsible for TGF-β-mediated cell growth inhibition in Chinese hamster ovary (CHO) cells. The LRP1 adapter protein GULP mediates internalization of the various LRP1-specific ligands, and we hypothesize that GULP acts as a novel regulator of TGF-β signaling in ovarian cells. CHO cells that overexpress exogenous GULP (FL) demonstrate enhancement in growth inhibition, migration, and invasion from TGF-β treatment, whereas cells that lack GULP (AS) show impairment of growth inhibition and decreased migration and invasion. The enhanced TGF-β response in FL cells was confirmed by a prolonged TGF-β-induced SMAD3 phosphorylation, whereas a shortening of the phosphorylation event is observed in AS cells. Mechanistically, the presence of GULP retains the TGF-β in a signaling-competent early endosome for enhanced signaling. To address this mechanism in a physiological setting, TGF-β insensitive ovarian adenocarcinoma cells (HEY) have a very low GULP expression level, similar to the observation made in a wide selection of human ovarian adenocarcinomas. Transfection of GULP into the HEY cells restored the TGF-β responsiveness, as measured by SMAD3 phosphorylation and impairment of cell growth. Because GULP expression positively regulates TGF-β signaling leading to growth inhibition, this may represent an attractive target to achieve TGF-β responsiveness in ovarian cells.
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Cheng-I J
authors.initials: CI
authors.lastname: Ma
authors.forename: Cyril
authors.initials: C
authors.lastname: Martin
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ma
authors.forename: Anouar
authors.initials: A
authors.lastname: Hafiane
authors.forename: Meiou
authors.initials: M
authors.lastname: Dai
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lebrun
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kiss
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016466:CHO Cells; D002465:Cell Movement; D006224:Cricetinae; D003412:Cricetulus; D011992:Endosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C454119:GULP1 protein, human; D009363:Neoplasm Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta