ALS2/Alsin regulates Rac-PAK signaling and neurite outgrowth.
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.
Tudor
Elizabeth L
EL
Departments of Neuroscience and Neurology, Institute of Psychiatry, Kings College, London SE5 8AF, United Kingdom.
Perkinton
Michael S
MS
Schmidt
Anja
A
Ackerley
Steven
S
Brownlees
Janet
J
Jacobsen
Nicholas J O
NJ
Byers
Helen L
HL
Ward
Malcolm
M
Hall
Alan
A
Leigh
P Nigel
PN
Shaw
Christopher E
CE
McLoughlin
Declan M
DM
Miller
Christopher C J
CC
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
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