title: ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth.
abstract: Rac and its downstream effectors p21-activated kinase (PAK) family kinases regulate actin dynamics within growth cones to control neurite outgrowth during development. The activity of Rac is stimulated by guanine nucleotide exchange factors (GEFs) that promote GDP release and GTP binding. ALS2/Alsin is a recently described GEF that contains a central domain that is predicted to regulate the activities of Rac and/or Rho and Cdc42 activities. Mutations in ALS2 cause some recessive familial forms of amyotrophic lateral sclerosis (ALS) but the function of ALS2 is poorly understood. Here we demonstrate that ALS2 is present within growth cones of neurons, in which it co-localizes with Rac. Furthermore, ALS2 stimulates Rac but not Rho or Cdc42 activities, and this induces a corresponding increase in PAK1 activity. Finally, we demonstrate that ALS2 promotes neurite outgrowth. Defects in these functions may therefore contribute to motor neuron demise in ALS.
authors.affiliation: Departments of Neuroscience and Neurology, Institute of Psychiatry, Kings College, London SE5 8AF, United Kingdom.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Tudor
authors.forename: Michael S
authors.initials: MS
authors.lastname: Perkinton
authors.forename: Anja
authors.initials: A
authors.lastname: Schmidt
authors.forename: Steven
authors.initials: S
authors.lastname: Ackerley
authors.forename: Janet
authors.initials: J
authors.lastname: Brownlees
authors.forename: Nicholas J O
authors.initials: NJ
authors.lastname: Jacobsen
authors.forename: Helen L
authors.initials: HL
authors.lastname: Byers
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ward
authors.forename: Alan
authors.initials: A
authors.lastname: Hall
authors.forename: P Nigel
authors.initials: PN
authors.lastname: Leigh
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
authors.forename: Declan M
authors.initials: DM
authors.lastname: McLoughlin
authors.forename: Christopher C J
authors.initials: CC
authors.lastname: Miller
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D009046:Motor Neurons / Q000378:metabolism; D016296:Mutagenesis; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014162:Transfection; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases
chemical_list: C438187:ALS2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D049452:Green Fluorescent Proteins; C515903:PAK1 protein, human; C515906:Pak1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D020558:GTP Phosphohydrolases; D020764:cdc42 GTP-Binding Protein