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Molecular and Cellular Biology, September 2007, p. 6001-6011, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.01807-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Nckß Adapter Controls Neuritogenesis by Maintaining the Cellular Paxillin Level{triangledown}

Shengxi Guan,1 Mei Chen,1 David Woodley,1,2 and Wei Li1,2*

Department of Dermatology and USC/Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90033,1 VA Greater Los Angeles Healthcare System, Sepulveda, California 913432

Received 22 September 2006/ Returned for modification 16 November 2006/ Accepted 14 June 2007

The SH2/SH3 adapter Nck has an evolutionarily conserved role in neurons, linking the cell surface signals to actin cytoskeleton-mediated responses. The mechanism, however, remains poorly understood. We have investigated the role of Nck/Nck{alpha}/Nck1 versus Grb4/Nckß/Nck2 side-by-side in the process of mammalian neuritogenesis. Here we show that permanent genetic silencing of Nckß, but not Nck{alpha}, completely blocked nerve growth factor-induced neurite outgrowth in PC12 cells and dramatically disrupted the axon and dendrite tree in primary rat cortical neurons. By screening for changes among the components reportedly present in complex with Nck, we found that the steady-state level of paxillin was significantly reduced in Nckß knockdown, but not Nck{alpha} knockdown, neurons. Interestingly, Nckß knockdown did not affect the paxillin level in glial cells and several other cell types of various tissue origins. Genetic silencing of paxillin blocked neuritogenesis, just like Nckß knockdown. Reintroducing a nondegradable Nckß into Nckß short interfering RNA-expressing PC12 cells rescued paxillin from down-regulation and allowed the resumption of neuritogenesis. Forced expression of paxillin in Nckß knockdown PC12 also rescued its capacity for neuritogenesis. Finally, Nckß, but not Nck{alpha}, binds strongly to paxillin and treatment of the neurons with proteosome inhibitors prevented paxillin down-regulation in Nckß knockdown neurons. Thus, Nckß maintains paxillin stability during neuritogenesis.

* Corresponding author. Mailing address: 1303 North Mission Road, Los Angeles, CA 90033. Phone: (323) 224-7058. Fax: (323) 224-7679. E-mail: wli{at}usc.edu

{triangledown} Published ahead of print on 25 June 2007.

Molecular and Cellular Biology, September 2007, p. 6001-6011, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.01807-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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