Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motility.
Lis1 gene defects impair neuronal migration, causing the severe human brain malformation lissencephaly. Although much is known about its interactions with microtubules, microtubule-binding proteins such as CLIP-170, and with the dynein motor complex, the response of Lis1 to neuronal motility signals has not been elucidated. Lis1 deficiency is associated with deregulation of the Rho-family GTPases Cdc42, Rac1 and RhoA, and ensuing actin cytoskeletal defects, but the link between Lis1 and Rho GTPases remains unclear. We report here that calcium influx enhances neuronal motility through Lis1-dependent regulation of Rho GTPases. Lis1 promotes Cdc42 activation through interaction with the calcium sensitive GTPase scaffolding protein IQGAP1, maintaining the perimembrane localization of IQGAP1 and CLIP170 and thereby tethering microtubule ends to the cortical actin cytoskeleton. Lis1 thus is a key component of neuronal motility signal transduction that regulates the cytoskeleton by complexing with IQGAP1, active Cdc42 and CLIP-170 upon calcium influx.
Kholmanskikh
Stanislav S
SS
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA.
Koeller
Hajira B
HB
Wynshaw-Boris
Anthony
A
Gomez
Timothy
T
Letourneau
Paul C
PC
Ross
M Elizabeth
ME
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000199:Actins / Q000378:metabolism; D000814:Aniline Compounds; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D014162:Transfection; D014966:Xanthenes; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D000814:Aniline Compounds; C409648:Fluo 4; D005456:Fluorescent Dyes; C101203:IQ motif containing GTPase activating protein 1; D008869:Microtubule-Associated Proteins; D014966:Xanthenes; D020703:ras GTPase-Activating Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse; D020764:cdc42 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D002118:Calcium