Nature Neuroscience 9, 50 - 57 (2005)
Published online: 20 December 2005; | doi:10.1038/nn1619
Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronal motilityStanislav S Kholmanskikh1, Hajira B Koeller1, Anthony Wynshaw-Boris2, Timothy Gomez3, Paul C Letourneau4
& M Elizabeth Ross11
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10021, USA. 2
Department of Pediatrics, University of California San Diego, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093, USA. 3
Department of Neuroscience, University of Wisconsin Medical School, 1300 University Avenue, Madison, Wisconsin 53706, USA. 4
Department of Neuroscience, University of Minnesota, 321 Church Street, Minneapolis, Minnesota 55455, USA.
Correspondence should be addressed to M Elizabeth Ross mer2005@med.cornell.edu
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.
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