MyosinV controls PTEN function and neuronal cell size.
The tumour suppressor PTEN can inhibit cell proliferation and migration as well as control cell growth, in different cell types. PTEN functions predominately as a lipid phosphatase, converting PtdIns(3,4,5)P(3) to PtdIns(4,5)P(2), thereby antagonizing PI(3)K (phosphoinositide 3-kinase) and its established downstream effector pathways. However, much is unclear concerning the mechanisms that regulate PTEN movement to the cell membrane, which is necessary for its activity towards PtdIns(3,4,5)P(3) (Refs 3, 4, 5). Here we show a requirement for functional motor proteins in the control of PI3K signalling, involving a previously unknown association between PTEN and myosinV. FRET (Förster resonance energy transfer) measurements revealed that PTEN interacts directly with myosinV, which is dependent on PTEN phosphorylation mediated by CK2 and/or GSK3. Inactivation of myosinV-transport function in neurons increased cell size, which, in line with known attributes of PTEN-loss, required PI(3)K and mTor. Our data demonstrate a myosin-based transport mechanism that regulates PTEN function, providing new insights into the signalling networks regulating cell growth.
van Diepen
Michiel T
MT
MRC Centre for Developmental Neurobiology, New Hunt's House, King's College London, London SE1 1UL, UK.
Parsons
Maddy
M
Downes
C Peter
CP
Leslie
Nicholas R
NR
Hindges
Robert
R
Eickholt
Britta J
BJ
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D048429:Cell Size; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D024701:Myosin Type V / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection
C541490:CKT2 protein, mouse; D010750:Phosphoproteins; D049452:Green Fluorescent Proteins; D001224:Aspartic Acid; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D024701:Myosin Type V; D000409:Alanine