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Activation of p107 by Fibroblast Growth Factor, Which Is Essential for Chondrocyte Cell Cycle Exit, Is Mediated by the Protein Phosphatase 2A/B55α Holoenzyme

Kurimchak, Alison and Haines, Dale S. and Garriga, Judit and Wu, Shufang and De Luca, Francesco and Sweredoski, Michael J. and Deshaies, Raymond J. and Hess, Sonja and Graña, Xavier (2013) Activation of p107 by Fibroblast Growth Factor, Which Is Essential for Chondrocyte Cell Cycle Exit, Is Mediated by the Protein Phosphatase 2A/B55α Holoenzyme. Molecular and Cellular Biology, 33 (16). pp. 3330-3342. ISSN 0270-7306. PMCID PMC3753905. doi:10.1128/MCB.00082-13.

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The phosphorylation state of pocket proteins during the cell cycle is determined at least in part by an equilibrium between inducible cyclin-dependent kinases (CDKs) and serine/threonine protein phosphatase 2A (PP2A). Two trimeric holoenzymes consisting of the core PP2A catalytic/scaffold dimer and either the B55α or PR70 regulatory subunit have been implicated in the activation of p107/p130 and pRB, respectively. While the phosphorylation state of p107 is very sensitive to forced changes of B55α levels in human cell lines, regulation of p107 in response to physiological modulation of PP2A/B55α has not been elucidated. Here we show that fibroblast growth factor 1 (FGF1), which induces maturation and cell cycle exit in chondrocytes, triggers rapid accumulation of p107-PP2A/B55α complexes coinciding with p107 dephosphorylation. Reciprocal solution-based mass spectrometric analysis identified the PP2A/B55α complex as a major component in p107 complexes, which also contain E2F/DPs, DREAM subunits, and/or cyclin/CDK complexes. Of note, p107 is one of the preferred partners of B55α, which also associates with pRB in RCS cells. FGF1-induced dephosphorylation of p107 results in its rapid accumulation in the nucleus and formation of larger complexes containing p107 and enhances its interaction with E2F4 and other p107 partners. Consistent with a key role of B55α in the rapid activation of p107 in chondrocytes, limited ectopic expression of B55α results in marked dephosphorylation of p107 while B55α knockdown results in hyperphosphorylation. More importantly, knockdown of B55α dramatically delays FGF1-induced dephosphorylation of p107 and slows down cell cycle exit. Moreover, dephosphorylation of p107 in response to FGF1 treatment results in early recruitment of p107 to the MYC promoter, an FGF1/E2F-regulated gene. Our results suggest a model in which FGF1 mediates rapid dephosphorylation and activation of p107 independently of the CDK activities that maintain p130 and pRB hyperphosphorylation for several hours after p107 dephosphorylation in maturing chondrocytes.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Sweredoski, Michael J.0000-0003-0878-3831
Deshaies, Raymond J.0000-0002-3671-9354
Hess, Sonja0000-0002-5904-9816
Additional Information:© 2013 American Society for Microbiology. Received 18 January 2013; Returned for modification 12 February 2013. Accepted 10 June 2013. Published ahead of print 17 June 2013. We thank Victoria Kolupaeva and Claudio Basilico for helpful discussions and reagents. We thank Geoffrey T. Smith for technical assistance. This work was supported, in part, by National Institutes of Health grant MH083585 to X.G. This work was also supported by a grant from the Pennsylvania Department of Health to X.G. S.H. and M.J.S. were supported by the Beckman Institute and the Gordon and Betty Moore Foundation through grant GBMF775.
Funding AgencyGrant Number
Pennsylvania Department of HealthUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Gordon and Betty Moore FoundationGBMF775
Issue or Number:16
PubMed Central ID:PMC3753905
Record Number:CaltechAUTHORS:20130904-105931353
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:41082
Deposited By: Tony Diaz
Deposited On:16 Sep 2013 21:56
Last Modified:10 Nov 2021 04:25

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