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

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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.

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Gene Ontology Annotations

Biological Process

cellular response to growth factor stimulus (IDA)

negative regulation of G0 to G1 transition (IDA)

positive regulation of neuron projection development (IDA)

positive regulation of neurotrophin TRK receptor signaling pathway (IDA,IMP)

positive regulation of protein autophosphorylation (IDA)

positive regulation of protein-containing complex assembly (IDA)

positive regulation of Ras protein signal transduction (IMP)

positive regulation of transcription by RNA polymerase II (IDA,IMP)

regulation of cell cycle (IDA)

regulation of peptidyl-tyrosine phosphorylation (IMP)

regulation of protein autophosphorylation (IDA,IMP)

regulation of protein catabolic process (IMP)

regulation of protein phosphorylation (IDA,IMP)

Cellular Component

cell surface (IDA)

protein phosphatase type 2A complex (IMP)

Molecular Function

identical protein binding (IMP)

protein tyrosine kinase activity (IDA)

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)

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