Nucleoside diphosphate kinase, a source of GTP, is required for dynamin-dependent synaptic vesicle recycling.
Nucleoside diphosphate kinase (NDK), an enzyme encoded by the Drosophila abnormal wing discs (awd) or human nm23 tumor suppressor genes, generates nucleoside triphosphates from respective diphosphates. We demonstrate that NDK regulates synaptic vesicle internalization at the stage where function of the dynamin GTPase is required. awd mutations lower the temperature at which behavioral paralysis, synaptic failure, and blocked membrane internalization occur at dynamin-deficient, shi(ts), mutant nerve terminals. Hypomorphic awd alleles display shi(ts)-like defects. NDK is present at synapses and its enzymatic activity is essential for normal presynaptic function. We suggest a model in which dynamin activity in nerve terminals is highly dependent on NDK-mediated supply of GTP. This connection between NDK and membrane internalization further strengthens an emerging hypothesis that endocytosis, probably of activated growth factor receptors, is an important tumor suppressor activity in vivo.
Krishnan
K S
KS
Department of Biological Sciences, Tata Institute for Fundamental Research, Homi Bhabha Road, 400005, Colaba, Bombay, India.
Rikhy
R
R
Rao
S
S
Shivalkar
M
M
Mosko
M
M
Narayanan
R
R
Etter
P
P
Estes
P S
PS
Ramaswami
M
M
D000483:Alleles; D000818:Animals; D001831:Body Temperature / Q000235:genetics; D001921:Brain / Q000378:metabolism; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics; D034281:Dynamins; D004705:Endocytosis / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000096:biosynthesis*; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D054778:NM23 Nucleoside Diphosphate Kinases; D009361:Neoplasm Invasiveness / Q000235:genetics; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism*; D010243:Paralysis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D017729:Presynaptic Terminals / Q000201:enzymology* / Q000648:ultrastructure; D021381:Protein Transport / Q000235:genetics; D013572:Synaptic Vesicles / Q000201:enzymology* / Q000648:ultrastructure; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; D019476:Insect Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; D014157:Transcription Factors; D006160:Guanosine Triphosphate; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; C061642:awd protein, Drosophila; D020558:GTP Phosphohydrolases; D020559:Monomeric GTP-Binding Proteins; D034281:Dynamins