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

2007 ◽  
Vol 19 (1) ◽  
pp. 139-151 ◽  
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

scholarly journals A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling

2003 ◽  
Vol 373 (2) ◽  
pp. 451-463 ◽  
Author(s):  
Mariko HATAKEYAMA ◽  
Shuhei KIMURA ◽  
Takashi NAKA ◽  
Takuji KAWASAKI ◽  
Noriko YUMOTO ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Protein Kinase ◽  
Cross Talk ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Mitogen Activated Protein Kinase ◽  
Regulation Mechanism ◽  
Erbb4 Receptor ◽  
Mitogen Activated Protein ◽  
Phosphatase 2A

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.

scholarly journals 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

2007 ◽  
Vol 27 (12) ◽  
pp. 4217-4227 ◽  
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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