Overexpression of the protein phosphatase 2A regulatory subunit Bgamma promotes neuronal differentiation by activating the MAP kinase (MAPK) cascade.
Protein serine/threonine phosphatase 2A (PP2A) is a multifunctional regulator of cellular signaling. Variable regulatory subunits associate with a core dimer of scaffolding and catalytic subunits and are postulated to dictate substrate specificity and subcellular location of the heterotrimeric PP2A holoenzyme. The role of brain-specific regulatory subunits in neuronal differentiation and signaling was investigated in the PC6-3 subline of PC12 cells. Endogenous Bbeta, Bgamma, and B'beta protein expression was induced during nerve growth factor (NGF)-mediated neuronal differentiation. Transient expression of Bgamma, but not other PP2A regulatory subunits, facilitated neurite outgrowth in the absence and presence of NGF. Tetracycline-inducible expression of Bgamma caused growth arrest and neurofilament expression, further evidence that PP2A/Bgamma can promote differentiation. In PC6-3 cells, but not non-neuronal cell lines, Bgamma specifically promoted long lasting activation of the mitogen-activated protein (MAP) kinase cascade, a key mediator of neuronal differentiation. Pharmacological and dominant-negative inhibition and kinase assays indicate that Bgamma promotes neuritogenesis by stimulating the MAP kinase cascade downstream of the TrkA NGF receptor but upstream or at the level of the B-Raf kinase. Mutational analyses demonstrate that the divergent N terminus is critical for Bgamma activity. These studies implicate PP2A/Bgamma as a positive regulator of MAP kinase signaling in neurons.
Department of Pharmacology, University of Iowa, College of Medicine, Iowa City 52242, USA. stefan-strack@uiowa.edu
Stefan
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Strack
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D004789:Enzyme Activation; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000502:physiology
C086766:Ppp2r1b protein, mouse; D020800:Receptor, Nerve Growth Factor; C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D010749:Phosphoprotein Phosphatases; C522189:Ppp2r1b protein, rat; D054648:Protein Phosphatase 2