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Molecular and Cellular Biology, June 2007, p. 4217-4227, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00067-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cytokine Activation of p38 Mitogen-Activated Protein Kinase and Apoptosis Is Opposed by alpha-4 Targeting of Protein Phosphatase 2A for Site-Specific Dephosphorylation of MEK3{triangledown} ,{dagger}

Todd D. Prickett and David L. Brautigan*

Center for Cell Signaling and Department of Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia 22908

Received 12 January 2007/ Returned for modification 9 February 2007/ Accepted 26 March 2007

alpha-4 is an essential gene and is a dominant antiapoptotic factor in various tissues that is a regulatory subunit for type 2A protein phosphatases. A multiplexed phosphorylation site screen revealed that knockdown of alpha-4 by small interfering RNA (siRNA) increased p38 mitogen-activated protein kinase (MAPK) and c-Jun phosphorylation without changes in JNK or ERK. FLAG-alpha-4 coprecipitated hemagglutinin-MEK3 plus endogenous protein phosphatase 2A (PP2A) and selectively enhanced dephosphorylation of Thr193, but not Ser189, in the activation loop of MEK3. Overexpression of alpha-4 suppressed p38 MAPK activation in response to tumor necrosis factor alpha (TNF-{alpha}). The alpha-4 dominant-negative domain (DND) (residues 220 to 340) associated with MEK3, but not PP2A, and its overexpression sensitized cells to activation of p38 MAPK by TNF-{alpha} and interleukin-1ß, but not by ansiomycin or sorbitol. The response was diminished by nocodazole or by siRNA knockdown of the Opitz syndrome protein Mid1 that binds alpha-4 to microtubules. Interference by alpha-4 DND or alpha-4 siRNA increased caspase 3/7 activation in response to TNF-{alpha}. Growth of transformed cells in soft agar was enhanced by alpha-4 and suppressed by alpha-4 DND. The results show that alpha-4 targets PP2A activity to MEK3 to suppress p38 MAPK activation by cytokines, thereby inhibiting apoptosis and anoikis.

* Corresponding author. Mailing address: Center for Cell Signaling and Department of Microbiology, University of Virginia School of Medicine, Jefferson Park Avenue, Hospital West Complex, Room 7225, Charlottesville, VA 229081400. Phone: (434) 924-5892. Fax: (434) 243-2829. E-mail: db8g{at}virginia.edu

{triangledown} Published ahead of print on 16 April 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2007, p. 4217-4227, Vol. 27, No. 12
0270-7306/07/$08.00+0     doi:10.1128/MCB.00067-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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