scholarly journals p38 mitogen-activated protein kinase dephosphorylation is regulated by protein phosphatase 2A in human platelets activated by collagen

FEBS Letters ◽  
2002 ◽  
Vol 528 (1-3) ◽  
pp. 139-144 ◽  
Author(s):  
Pavithra Sundaresan ◽  
Richard W Farndale
Keyword(s):  
Protein Kinase ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Human Platelets ◽  
Mitogen Activated Protein Kinase ◽  
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.

scholarly journals The Serine/Threonine Protein Phosphatase 2A (PP2A) Regulates Syk Activity in Human Platelets

2020 ◽  
Vol 21 (23) ◽  
pp. 8939
Author(s):  
Stephanie Makhoul ◽  
Elena Kumm ◽  
Pengyu Zhang ◽  
Ulrich Walter ◽  
Kerstin Jurk
Keyword(s):  
Protein Kinase ◽  
Platelet Activation ◽  
Protein Phosphatase ◽  
Feedback Inhibition ◽  
Protein Phosphatase 2A ◽  
Human Platelets ◽  
Membrane Receptors ◽  
Functional Link ◽  
S Protein ◽  
Phosphatase 2A

Distinct membrane receptors activate platelets by Src-family-kinase (SFK)-, immunoreceptor-tyrosine-based-activation-motif (ITAM)-dependent stimulation of spleen tyrosine kinase (Syk). Recently, we reported that platelet activation via glycoprotein (GP) VI or GPIbα stimulated the well-established Syk tyrosine (Y)-phosphorylation, but also stoichiometric, transient protein kinase C (PKC)-mediated Syk serine(S)297 phosphorylation in the regulatory interdomain-B, suggesting possible feedback inhibition. The transient nature of Syk S297 phosphorylation indicated the presence of an unknown Syk pS297 protein phosphatase. In this study, we hypothesize that the S-protein phosphatase 2A (PP2A) is responsible for Syk pS297 dephosphorylation, thereby affecting Syk Y-phosphorylation and activity in human washed platelets. Using immunoblotting, we show that specific inhibition of PP2A by okadaic acid (OA) alone leads to stoichiometric Syk S297 phosphorylation, as analyzed by Zn2+-Phos-tag gels, without affecting Syk Y-phosphorylation. Pharmacological inhibition of Syk by PRT060318 or PKC by GF109203X only minimally reduced OA-induced Syk S297 phosphorylation. PP2A inhibition by OA preceding GPVI-mediated platelet activation induced by convulxin extended Syk S297 phosphorylation but inhibited Syk Y-phosphorylation. Our data demonstrate a novel biochemical and functional link between the S-protein phosphatase PP2A and the Y-protein kinase Syk in human platelets, and suggest that PP2A represents a potential enhancer of GPVI-mediated Syk activity caused by Syk pS297 dephosphorylation.

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