TY - JOUR
T1 - Mical links semaphorins to F-actin disassembly
AU - Hung, Ruei Jiun
AU - Yazdani, Umar
AU - Yoon, Jimok
AU - Wu, Heng
AU - Yang, Taehong
AU - Gupta, Nidhi
AU - Huang, Zhiyu
AU - Van Berkel, Willem J H
AU - Terman, Jonathan R.
N1 - Funding Information:
Acknowledgements We thank C. Cowan, M. Rosen and T. Südhof for comments on drafts of our manuscript and M. Bailey, C. Gilpin, H. He, T. Januszewski, H. Krämer, W. Lin, T. Wedgeworth, X. Zhang and the University of Texas Southwestern Electron Microscopy Core Facility for discussions and assistance. We also thank the Bloomington, Harvard and Japanese stock centres for flies and H. Aberle, L. Cooley, C. Goodman, A. Kolodkin, B. Lee, L. Luo, J. Merriam and X. Zhang for flies and/or reagents. This work was supported by the US National Institute of Mental Health (MH085923) and a Basil O’Connor Starter Scholar Research Award to J.R.T. J.R.T. is a Klingenstein Fellow and the Rita C. and William P. Clements, Jr, Scholar in Medical Research.
PY - 2010/2/11
Y1 - 2010/2/11
N2 - How instructive cues present on the cell surface have their precise effects on the actin cytoskeleton is poorly understood. Semaphorins are one of the largest families of these instructive cues and are widely studied for their effects on cell movement, navigation, angiogenesis, immunology and cancer. Semaphorins/collapsins were characterized in part on the basis of their ability to drastically alter actin cytoskeletal dynamics in neuronal processes, but despite considerable progress in the identification of semaphorin receptors and their signalling pathways, the molecules linking them to the precise control of cytoskeletal elements remain unknown. Recently, highly unusual proteins of the Mical family of enzymes have been found to associate with the cytoplasmic portion of plexins, which are large cell-surface semaphorin receptors, and to mediate axon guidance, synaptogenesis, dendritic pruning and other cell morphological changes. Mical enzymes perform reduction-oxidation (redox) enzymatic reactions and also contain domains found in proteins that regulate cell morphology. However, nothing is known of the role of Mical or its redox activity in mediating morphological changes. Here we report that Mical directly links semaphorins and their plexin receptors to the precise control of actin filament (F-actin) dynamics. We found that Mical is both necessary and sufficient for semaphorin-plexin-mediated F-actin reorganization in vivo. Likewise, we purified Mical protein and found that it directly binds F-actin and disassembles both individual and bundled actin filaments. We also found that Mical utilizes its redox activity to alter F-actin dynamics in vivo and in vitro, indicating a previously unknown role for specific redox signalling events in actin cytoskeletal regulation. Mical therefore is a novel F-actin-disassembly factor that provides a molecular conduit through which actin reorganizationa hallmark of cell morphological changes including axon navigationcan be precisely achieved spatiotemporally in response to semaphorins.
AB - How instructive cues present on the cell surface have their precise effects on the actin cytoskeleton is poorly understood. Semaphorins are one of the largest families of these instructive cues and are widely studied for their effects on cell movement, navigation, angiogenesis, immunology and cancer. Semaphorins/collapsins were characterized in part on the basis of their ability to drastically alter actin cytoskeletal dynamics in neuronal processes, but despite considerable progress in the identification of semaphorin receptors and their signalling pathways, the molecules linking them to the precise control of cytoskeletal elements remain unknown. Recently, highly unusual proteins of the Mical family of enzymes have been found to associate with the cytoplasmic portion of plexins, which are large cell-surface semaphorin receptors, and to mediate axon guidance, synaptogenesis, dendritic pruning and other cell morphological changes. Mical enzymes perform reduction-oxidation (redox) enzymatic reactions and also contain domains found in proteins that regulate cell morphology. However, nothing is known of the role of Mical or its redox activity in mediating morphological changes. Here we report that Mical directly links semaphorins and their plexin receptors to the precise control of actin filament (F-actin) dynamics. We found that Mical is both necessary and sufficient for semaphorin-plexin-mediated F-actin reorganization in vivo. Likewise, we purified Mical protein and found that it directly binds F-actin and disassembles both individual and bundled actin filaments. We also found that Mical utilizes its redox activity to alter F-actin dynamics in vivo and in vitro, indicating a previously unknown role for specific redox signalling events in actin cytoskeletal regulation. Mical therefore is a novel F-actin-disassembly factor that provides a molecular conduit through which actin reorganizationa hallmark of cell morphological changes including axon navigationcan be precisely achieved spatiotemporally in response to semaphorins.
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U2 - 10.1038/nature08724
DO - 10.1038/nature08724
M3 - Article
C2 - 20148037
AN - SCOPUS:76749102917
SN - 0028-0836
VL - 463
SP - 823
EP - 827
JO - Nature
JF - Nature
IS - 7282
ER -