Mgat5 and Pten interact to regulate cell growth and polarity.
Phosphatase and tensin homolog (Pten) phosphatase opposes intracellular phosphoinositide 3-kinase (PI3K)/Akt signaling and is a potent tumor suppressor, while Golgi beta1,6 N-acetylglucosaminyltransferase V (Mgat5) is positively associated with cancer progression and metastasis. beta1,6GlcNAc-branched N-glycans on receptor glycoproteins promote their surface residency and sensitizes cells to growth factor signaling. Here we demonstrate that the Pten heterozygosity in mouse embryonic fibroblasts enhances cell adhesion-dependent PI3K/Akt signaling, cell spreading, and proliferation, while Pten/Mgat5 double mutant cells are normalized. However, planar asymmetry typical of fibroblasts and invasive carcinomas is not fully rescued, suggesting that Mgat5 and Pten function together to regulate the membrane dynamics of PI3K/Akt signaling typical of motile cells. Pten heterozygosity was associated with increased surface beta1,6GlcNAc-branched N-glycans, suggesting positive feedback from PI3K signaling to N-glycan branching. In vivo, Mgat5(-/-) Pten(+/-) and Mgat5(+/-)Pten(+/-)mutant mice showed a small but significant increase in longevity compared with Pten(+/-) mice. Taken together, our results reveal that Mgat5 and Pten interact in an opposing manner to regulate cellular sensitivities to extracelluar growth cues.
Cheung
Pam
P
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, R988 Toronto, Ontario, Canada M5G 1X5.
Dennis
James W
JW
D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004843:Epistasis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000737:chemistry / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000502:physiology*; D013499:Surface Properties
D017351:N-Acetylglucosaminyltransferases; C510765:N-acetylglucosaminyltransferase IX, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse