title: Ndfip1 represses cell proliferation by controlling Pten localization and signaling specificity.
abstract: Pten controls a signaling axis that is implicated to regulate cell proliferation, growth, survival, migration, and metabolism. The molecular mechanisms underlying the specificity of Pten responses to such diverse cellular functions are currently poorly understood. Here we report the control of Pten activity and signaling specificity during the cell cycle by Ndfip1 regulation of Pten spatial distribution. Genetic deletion of Ndfip1 resulted in a loss of Pten nuclear compartmentalization and increased cell proliferation, despite cytoplasmic Pten remaining active in regulating PI3K/Akt signaling. Cells lacking nuclear Pten were found to have dysregulated levels of Plk1 and cyclin D1 that could drive cell proliferation. In vivo, transgene expression of Ndfip1 in the developing brain increased nuclear Pten and lengthened the cell cycle of neuronal progenitors, resulting in microencephaly. Our results show that local partitioning of Pten from the cytoplasm to the nucleus represents a key mechanism contributing to the specificity of Pten signaling during cell proliferation.
authors: Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia jason.howitt@florey.edu.au stan@florey.edu.au.
authors: Jason
authors: J
authors: Howitt
authors: Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Ley-Hian
authors: LH
authors: Low
authors: Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Ulrich
authors: U
authors: Putz
authors: Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Anh
authors: A
authors: Doan
authors: Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Jenny
authors: J
authors: Lackovic
authors: Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Choo-Peng
authors: CP
authors: Goh
authors: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: Jenny
authors: J
authors: Gunnersen
authors: Cell Signalling and Cell Death Laboratory, Walter and Eliza Hall Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors: John
authors: J
authors: Silke
authors: Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia jason.howitt@florey.edu.au stan@florey.edu.au.
authors: Seong-Seng
authors: SS
authors: Tan
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D007191:Indazoles / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008831:Microcephaly / Q000378:metabolism; D016716:PC12 Cells; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D007191:Indazoles; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D020123:Sirolimus; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D000097869:Polo-Like Kinase 1; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C530105:Ccnd1 protein, mouse; C499188:Ndfip1 protein, mouse; C546843:mTOR protein, mouse; C487757:Pten protein, mouse
keywords: Akt; autism; cancer; cell cycle; microcephaly; nuclear trafficking; ubiquitin