NOS1AP associates with Scribble and regulates dendritic spine development.
The formation and function of the neuronal synapse is dependent on the asymmetric distribution of proteins both presynaptically and postsynaptically. Recently, proteins important in establishing cellular polarity have been implicated in the synapse. We therefore performed a proteomic screen with known polarity proteins and identified novel complexes involved in synaptic function. Specifically, we show that the tumor suppressor protein, Scribble, associates with neuronal nitric oxide synthase (nNOS) adaptor protein (NOS1AP) [also known as C-terminal PDZ ligand of nNOS (CAPON)] and is found both presynaptically and postsynaptically. The Scribble-NOS1AP association is direct and is mediated through the phosphotyrosine-binding (PTB) domain of NOS1AP and the fourth PDZ domain of Scribble. Further, we show that Scribble bridges NOS1AP to a beta-Pix [beta-p21-activated kinase (PAK)-interacting exchange factor]/Git1 (G-protein-coupled receptor kinase-interacting protein)/PAK complex. The overexpression of NOS1AP leads to an increase in dendritic protrusions, in a fashion that depends on the NOS1AP PTB domain. Consistent with these observations, both full-length NOS1AP and the NOS1AP PTB domain influence Rac activity. Together these data suggest that NOS1AP plays an important role in the mammalian synapse.
Richier
Lindsay
L
Departments of Pharmacology, Surgery, and Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.
Williton
Kelly
K
Clattenburg
Leanne
L
Colwill
Karen
K
O'Brien
Michael
M
Tsang
Christopher
C
Kolar
Annette
A
Zinck
Natasha
N
Metalnikov
Pavel
P
Trimble
William S
WS
Krueger
Stefan R
SR
Pawson
Tony
T
Fawcett
James P
JP
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D049229:Dendritic Spines / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D019000:Phosphotyrosine / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
C576606:ARHGEF7 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C485647:GIT1 protein, human; D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes; C488082:NOS1AP protein, rat; D020033:Protein Isoforms; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; C548802:scribble protein, rat; D019000:Phosphotyrosine; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins