RGD Reference Report - The protein phosphatase 2A regulatory subunits B'beta and B'delta mediate sustained TrkA neurotrophin receptor autophosphorylation and neuronal differentiation. - Rat Genome Database

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The protein phosphatase 2A regulatory subunits B'beta and B'delta mediate sustained TrkA neurotrophin receptor autophosphorylation and neuronal differentiation.

Authors: Van Kanegan, MJ  Strack, S 
Citation: Van Kanegan MJ and Strack S, Mol Cell Biol. 2009 Feb;29(3):662-74. doi: 10.1128/MCB.01242-08. Epub 2008 Nov 24.
RGD ID: 8553977
Pubmed: PMID:19029245   (View Abstract at PubMed)
PMCID: PMC2630673   (View Article at PubMed Central)
DOI: DOI:10.1128/MCB.01242-08   (Journal Full-text)

Nerve growth factor (NGF) is critical for the differentiation and maintenance of neurons in the peripheral and central nervous system. Sustained autophosphorylation of the TrkA receptor tyrosine kinase and long-lasting activation of downstream kinase cascades are hallmarks of NGF signaling, yet our knowledge of the molecular mechanisms underlying prolonged TrkA activity is incomplete. Protein phosphatase 2A (PP2A) is a heterotrimeric Ser/Thr phosphatase composed of a scaffolding, catalytic, and regulatory subunit (B, B', and B" gene families). Here, we employ a combination of pharmacological inhibitors, regulatory subunit overexpression, PP2A scaffold subunit exchange, and RNA interference to show that PP2A containing B' family regulatory subunits participates in sustained NGF signaling in PC12 cells. Specifically, two neuron-enriched regulatory subunits, B'beta and B'delta, recruit PP2A into a complex with TrkA to dephosphorylate the NGF receptor on Ser/Thr residues and to potentiate its intrinsic Tyr kinase activity. Acting at the receptor level, PP2A/ B'beta and B'delta enhance NGF (but not epidermal growth factor or fibroblast growth factor) signaling through the Akt and Ras-mitogen-activated protein kinase cascades and promote neuritogenesis and differentiation of PC12 cells. Thus, select PP2A heterotrimers oppose desensitization of the TrkA receptor tyrosine kinase, perhaps through dephosphorylation of inhibitory Ser/Thr phosphorylation sites on the receptor itself, to maintain neurotrophin-mediated developmental and survival signaling.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ntrk1Ratcellular response to growth factor stimulus acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatcellular response to growth factor stimulus acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatnegative regulation of G0 to G1 transition acts_upstream_of_or_withinIDA PMID:19029245MGI 
NgfRatpositive regulation of DNA-binding transcription factor activity acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatpositive regulation of DNA-binding transcription factor activity acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatpositive regulation of neuron projection development acts_upstream_of_or_withinIDA PMID:19029245MGI 
NgfRatpositive regulation of neurotrophin TRK receptor signaling pathway acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatpositive regulation of neurotrophin TRK receptor signaling pathway acts_upstream_of_or_withinIMP PMID:19029245MGI 
NgfRatpositive regulation of protein autophosphorylation acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatpositive regulation of protein-containing complex assembly acts_upstream_of_or_withinIDA PMID:19029245MGI 
HrasRatpositive regulation of Ras protein signal transduction acts_upstream_of_or_withinIMP PMID:19029245MGI 
Map2k1Ratpositive regulation of Ras protein signal transduction acts_upstream_of_or_withinIMP PMID:19029245MGI 
Elk1Ratpositive regulation of transcription by RNA polymerase II acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatpositive regulation of transcription by RNA polymerase II acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ntrk1Ratprotein autophosphorylation acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatregulation of cell cycle acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatregulation of peptidyl-tyrosine phosphorylation acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ppp2caRatregulation of protein autophosphorylation acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ppp2r5bRatregulation of protein autophosphorylation acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ppp2r5bRatregulation of protein autophosphorylation acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2caRatregulation of protein catabolic process acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ppp2caRatregulation of protein phosphorylation acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ppp2r5bRatregulation of protein phosphorylation acts_upstream_of_or_withinIDA PMID:19029245MGI 
Ppp2r5bRatregulation of protein phosphorylation acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ppp2caRatregulation of signaling receptor activity acts_upstream_of_or_withinIMP PMID:19029245MGI 
Ppp2r5bRatregulation of signaling receptor activity acts_upstream_of_or_withinIMP PMID:19029245MGI 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ntrk1Ratcell surface located_inIDA PMID:19029245MGI 
TfrcRatcell surface located_inIDA PMID:19029245MGI 
Ppp2caRatprotein phosphatase type 2A complex part_ofIMP PMID:19029245MGI 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ppp2caRatidentical protein binding enablesIMP PMID:19029245MGI 
Ntrk1Ratprotein tyrosine kinase activity enablesIDA PMID:19029245MGI 

Objects Annotated

Genes (Rattus norvegicus)
Elk1  (ETS transcription factor ELK1)
Hras  (HRas proto-oncogene, GTPase)
Map2k1  (mitogen activated protein kinase kinase 1)
Ngf  (nerve growth factor)
Ntrk1  (neurotrophic receptor tyrosine kinase 1)
Ppp2ca  (protein phosphatase 2 catalytic subunit alpha)
Ppp2r5b  (protein phosphatase 2, regulatory subunit B', beta)
Tfrc  (transferrin receptor)


Additional Information