A Role for Protein Phosphatase-2A in p38 Mitogen-activated Protein Kinase-mediated Regulation of the c-Jun NH2-terminal Kinase Pathway in Human Neutrophils

ErbB tyrosine kinase receptors mediate mitogenic signal cascade by binding a variety of ligands and recruiting the different cassettes of adaptor proteins. In the present study, we examined heregulin (HRG)-induced signal transduction of ErbB4 receptor and found that the phosphatidylinositol 3′-kinase (PI3K)-Akt pathway negatively regulated the extracellular signal-regulated kinase (ERK) cascade by phosphorylating Raf-1 on Ser259. As the time-course kinetics of Akt and ERK activities seemed to be transient and complex, we constructed a mathematical simulation model for HRG-induced ErbB4 receptor signalling to explain the dynamics of the regulation mechanism in this signal transduction cascade. The model reflected well the experimental results observed in HRG-induced ErbB4 cells and in other modes of growth hormone-induced cell signalling that involve Raf-Akt cross-talk. The model suggested that HRG signalling is regulated by protein phosphatase 2A as well as Raf-Akt cross-talk, and protein phosphatase 2A modulates the kinase activity in both the PI3K–Akt and MAPK (mitogen-activated protein kinase) pathways.

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Regulation of Spindle Formation by Active Mitogen-Activated Protein Kinase and Protein Phosphatase 2A During Mouse Oocyte Meiosis1

Biology of Reproduction ◽

10.1095/biolreprod66.1.29 ◽

2002 ◽

Vol 66 (1) ◽

pp. 29-37 ◽

Cited By ~ 36

Author(s):

Qing Lu ◽

Rodney L. Dunn ◽

Rowena Angeles ◽

Gary D. Smith

Keyword(s):

Protein Kinase ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Mouse Oocyte ◽

Mitogen Activated Protein Kinase ◽

Spindle Formation ◽

Mitogen Activated Protein ◽

Phosphatase 2A

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Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase

Cellular Signalling ◽

10.1016/j.cellsig.2006.05.030 ◽

2007 ◽

Vol 19 (1) ◽

pp. 139-151 ◽

Cited By ~ 43

Author(s):

Robert T.M. Boudreau ◽

David M. Conrad ◽

David W. Hoskin

Keyword(s):

Protein Kinase ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Mitogen Activated Protein Kinase ◽

Leukemia Cells ◽

Mitogen Activated Protein ◽

Phosphatase 2A

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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

Molecular and Cellular Biology ◽

10.1128/mcb.00067-07 ◽

2007 ◽

Vol 27 (12) ◽

pp. 4217-4227 ◽

Cited By ~ 40

Author(s):

Todd D. Prickett ◽

David L. Brautigan

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Phosphorylation Site ◽

Mitogen Activated Protein Kinase ◽

Mapk Activation ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Phosphatase 2A

ABSTRACT 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-α). 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-α and interleukin-1β, 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-α. 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.

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