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Molecular and Cellular Biology, November 2008, p. 6954-6966, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.00925-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinase 2 (ERK2) Phosphorylation Sites and Docking Domain on the Nuclear Pore Complex Protein Tpr Cooperatively Regulate ERK2-Tpr Interaction{triangledown}

Tomás Vomastek,3,§ Marcin P. Iwanicki,2,§ W. Richard Burack,4 Divya Tiwari,1 Devanand Kumar,1 J. Thomas Parsons,2 Michael J. Weber,2* and Vinay Kumar Nandicoori1*

National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110 067, India,1 Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, P.O. Box 800734, Charlottesville, Virginia 22908-0734,2 Cell and Molecular Microbiology Division, Institute of Microbiology, Prague, Czech Republic,3 University of Rochester Medical Center, 601 Elmwood Ave., Rochester, New York 14642-86264

Received 10 June 2008/ Returned for modification 1 August 2008/ Accepted 9 September 2008

Identifying direct substrates of mitogen-activated protein kinases (MAPKs) and understanding how those substrates are selected is central to understanding how these ubiquitously activated enzymes generate diverse biological responses. In previous work, we identified several new candidate substrates for the MAPK ERK2 (extracellular signal-regulated kinase 2), including the nuclear pore complex protein Tpr (translocated promoter region). In this report, we identify sites on Tpr for ERK2 phosphorylation and binding and demonstrate their functional interaction. ERK2 phosphorylation and dimerization are necessary for ERK2-Tpr binding, and this occurs through a DEF (docking site for ERK2, FXF) domain on Tpr. Surprisingly, the DEF domain and the phosphorylation sites displayed positive cooperativity to promote ERK2 binding to Tpr, in contrast to substrates where phosphorylation reduces binding. Ectopic expression or depletion of Tpr resulted in decreased movement of activated ERK2 from the cytoplasm to the nucleus, implying a role for Tpr in ERK2 translocation. Collectively, the data provide direct evidence that a component of the nuclear pore complex is a bona fide substrate of ERK2 in vivo and that activated ERK2 stably associates with this substrate after phosphorylation, where it could play a continuing role in nuclear pore function. We propose that Tpr is both a substrate and a scaffold for activated ERKs.

* Corresponding author. Mailing address for Vinay Kumar Nandicoori: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110 067, India. Phone: (91) 11-26703789. Fax: (91) 11-26742125. E-mail: vinaykn{at}nii.res.in. Mailing address for Michael J. Weber: Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, P.O. Box 800734, Charlottesville, VA 22908-0734. Phone: (434) 924-5022. Fax: (434) 982-0689. E-mail: mjw{at}virginia.edu

{triangledown} Published ahead of print on 15 September 2008.

§ These authors contributed equally to this work.

Molecular and Cellular Biology, November 2008, p. 6954-6966, Vol. 28, No. 22
0270-7306/08/$08.00+0     doi:10.1128/MCB.00925-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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