title: Identification of neuronal substrates implicates Pak5 in synaptic vesicle trafficking.
abstract: Synaptic transmission is mediated by a complex set of molecular events that must be coordinated in time and space. While many proteins that function at the synapse have been identified, the signaling pathways regulating these molecules are poorly understood. Pak5 (p21-activated kinase 5) is a brain-specific isoform of the group II Pak kinases whose substrates and roles within the central nervous system are largely unknown. To gain insight into the physiological roles of Pak5, we engineered a Pak5 mutant to selectively radiolabel its substrates in murine brain extract. Using this approach, we identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo. These results implicate Pak5 in Pacsin1- and Synaptojanin1-mediated synaptic vesicle trafficking and may partially account for the cognitive and behavioral deficits observed in group II Pak-deficient mice.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
authors.forename: Todd I
authors.initials: TI
authors.lastname: Strochlic
authors.forename: Susanna
authors.initials: S
authors.lastname: Concilio
authors.forename: Julien
authors.initials: J
authors.lastname: Viaud
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Eberwine
authors.forename: Lisa Epstein
authors.initials: LE
authors.lastname: Wong
authors.forename: Audrey
authors.initials: A
authors.lastname: Minden
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Markus
authors.initials: M
authors.lastname: Plomann
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Peterson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology*; D009479:Neuropeptides / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D013379:Substrate Specificity; D013572:Synaptic Vesicles / Q000201:enzymology*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C114726:Pacsin1 protein, mouse; D010750:Phosphoproteins; C486708:Pak7 protein, mouse; D054462:p21-Activated Kinases; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases