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Molecular and Cellular Biology, February 2009, p. 662-674, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01242-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Protein Phosphatase 2A Regulatory Subunits B'β and B'{delta} Mediate Sustained TrkA Neurotrophin Receptor Autophosphorylation and Neuronal Differentiation{triangledown}

Michael J. Van Kanegan and Stefan Strack*

Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa

Received 6 August 2008/ Returned for modification 24 August 2008/ Accepted 15 November 2008

Nerve growth factor (NGF) is critical for the differentiation and maintenance of neurons in the peripheral and central nervous system. Sustained autophosphorylation of the TrkA receptor tyrosine kinase and long-lasting activation of downstream kinase cascades are hallmarks of NGF signaling, yet our knowledge of the molecular mechanisms underlying prolonged TrkA activity is incomplete. Protein phosphatase 2A (PP2A) is a heterotrimeric Ser/Thr phosphatase composed of a scaffolding, catalytic, and regulatory subunit (B, B', and B" gene families). Here, we employ a combination of pharmacological inhibitors, regulatory subunit overexpression, PP2A scaffold subunit exchange, and RNA interference to show that PP2A containing B' family regulatory subunits participates in sustained NGF signaling in PC12 cells. Specifically, two neuron-enriched regulatory subunits, B'β and B'{delta}, recruit PP2A into a complex with TrkA to dephosphorylate the NGF receptor on Ser/Thr residues and to potentiate its intrinsic Tyr kinase activity. Acting at the receptor level, PP2A/ B'β and B'{delta} enhance NGF (but not epidermal growth factor or fibroblast growth factor) signaling through the Akt and Ras-mitogen-activated protein kinase cascades and promote neuritogenesis and differentiation of PC12 cells. Thus, select PP2A heterotrimers oppose desensitization of the TrkA receptor tyrosine kinase, perhaps through dephosphorylation of inhibitory Ser/Thr phosphorylation sites on the receptor itself, to maintain neurotrophin-mediated developmental and survival signaling.

* Corresponding author. Mailing address: Department of Pharmacology, University of Iowa Carver College of Medicine, 51 Newton Dr., Iowa City, IA 52242. Phone: (319) 384-4439. Fax: (319) 335-8930. E-mail: stefan-strack{at}uiowa.edu

{triangledown} Published ahead of print on 24 November 2008.

Molecular and Cellular Biology, February 2009, p. 662-674, Vol. 29, No. 3
0270-7306/09/$08.00+0     doi:10.1128/MCB.01242-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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