Ndfip1 represses cell proliferation by controlling Pten localization and signaling specificity

Jason Howitt; Ley-Hian Low; Ulrich Putz; Anh Doan; Jenny Lackovic; Choo-Peng Goh; Jenny Gunnersen; John Silke; Seong-Seng Tan

doi:10.1093/jmcb/mjv020

Ndfip1 represses cell proliferation by controlling Pten localization and signaling specificity

J Mol Cell Biol. 2015 Apr;7(2):119-31. doi: 10.1093/jmcb/mjv020. Epub 2015 Mar 23.

Authors

Jason Howitt¹, Ley-Hian Low², Ulrich Putz², Anh Doan², Jenny Lackovic², Choo-Peng Goh², Jenny Gunnersen³, John Silke⁴, Seong-Seng Tan¹

Affiliations

¹ 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.
² Brain Development and Regeneration Division, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.
³ Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia.
⁴ Cell Signalling and Cell Death Laboratory, Walter and Eliza Hall Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.

PMID: 25801959
DOI: 10.1093/jmcb/mjv020

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.

Keywords: Akt; autism; cancer; cell cycle; microcephaly; nuclear trafficking; ubiquitin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus
Animals
Carrier Proteins / physiology*
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation*
Cyclin D1 / metabolism
Female
Indazoles / pharmacology
Intercellular Signaling Peptides and Proteins
Membrane Proteins / physiology*
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Microcephaly / metabolism
PC12 Cells
PTEN Phosphohydrolase / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Polo-Like Kinase 1
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / metabolism
Rats
Signal Transduction
Sirolimus / pharmacology
Sulfonamides / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism

Substances

2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
Carrier Proteins
Ccnd1 protein, mouse
Cell Cycle Proteins
Indazoles
Intercellular Signaling Peptides and Proteins
Membrane Proteins
Ndfip1 protein, mouse
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins
Sulfonamides
Cyclin D1
mTOR protein, mouse
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
Pten protein, mouse
Sirolimus