PP2A: More than a reset switch to activate pRB proteins during the cell cycle and in response to signaling cues http://www.tandfonline.com/doi/pdf/10.4161/15384101.2014.985069

Cell Cycle

Volumn 14, Issue 1, 2015, Pages 18-30

  Kurimchak, Alison ^a   Graña, Xavier ^a  

^a TEMPLE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

B55 ; B55 ; Cell cycle; Chondrocyte; E2F; P107; P130; PP2A; PPP2R2A PP1; PR70; PRB; Retinoblastoma

Indexed keywords

CYCLIN DEPENDENT KINASE; FIBROBLAST GROWTH FACTOR 1; HOLOENZYME; PHOSPHOPROTEIN PHOSPHATASE; PHOSPHOPROTEIN PHOSPHATASE 2A; PHOSPHOPROTEIN PHOSPHATASE 2; PROTEIN SUBUNIT; RETINOBLASTOMA PROTEIN; TRANSCRIPTION FACTOR E2F;

CARTILAGE CELL; CELL CYCLE; HUMAN; MITOSIS; NONHUMAN; PROTEIN DEPHOSPHORYLATION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN QUATERNARY STRUCTURE; PROTEIN TARGETING; REVIEW; ANIMAL; CHEMISTRY; INTERPHASE; METABOLISM; OXIDATIVE STRESS; PHOSPHORYLATION; PROTEIN SUBUNIT; SIGNAL TRANSDUCTION;

ANIMALS; CYCLIN-DEPENDENT KINASES; E2F TRANSCRIPTION FACTORS; INTERPHASE; OXIDATIVE STRESS; PHOSPHORYLATION; PROTEIN PHOSPHATASE 2; PROTEIN SUBUNITS; RETINOBLASTOMA PROTEIN; SIGNAL TRANSDUCTION;

EID: 84921882819     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/15384101.2014.985069     Document Type: Review

References (125)

1. Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes Dev 2004; 18:2699-711; PMID:15545627; http://dx.doi.org/10.1101/gad.1256504
2. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13:1501-12; PMID:10385618; http://dx.doi.org/10.1101/gad.13.12.1501
3. Pei XH, Xiong Y. Biochemical and cellular mechanisms of mammalian CDK inhibitors: a few unresolved issues. Oncogene 2005; 24:2787-95; PMID:15838515; http://dx.doi.org/10.1038/sj.onc.1208611
4. Lim S, Kaldis P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013; 140:3079-93; PMID:23861057; http://dx.doi.org/10.1242/dev.091744
5. Dick FA, Rubin SM. Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 2013; 14:297-306; PMID:23594950; http://dx.doi.org/10.1038/nrm3567
6. MacDonald J, Dick FA. Posttranslational modifications of the retinoblastoma tumor suppressor protein as determinants of function. Genes & Cancer 2013; In Press.
7. Viatour P. Bridges between cell cycle regulation and self-renewal maintenance. Genes Cancer 2012; 3:670-7; PMID:23634255
8. Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971; 68:820-3; PMID:5279523
9. Classon M, Dyson N. p107 and p130: versatile proteins with interesting pockets. Exp Cell Res 2001; 264:135-47; PMID:11237530; http://dx.doi.org/10.1006/excr.2000.5135
10. Mulligan G, Jacks T. The retinoblastoma gene family: cousins with overlapping interests. Trends Genet 1998; 14:223-9; PMID:9635405; http://dx.doi.org/10.1016/S0168-9525(98)01470-X
11. Wirt SE, Sage J. p107 in the public eye: an Rb understudy and more. Cell Div 2010; 5:9; PMID:20359370; http://dx.doi.org/10.1186/1747-1028-5-9
12. Graña X, Garriga J, Mayol X. Role of the retinoblastoma protein family, pRB, p107 and p130 in the negative control of cell growth. Oncogene 1998; 17:3365-83; PMID:9916999; http://dx.doi.org/10.1038/sj.onc.1202575
13. Whyte P, Williamson NM, Harlow E. Cellular targets for transformation by the adenovirus E1A proteins. Cell 1989; 56:67-75; PMID:2521301; http://dx.doi.org/10.1016/0092-8674(89)90984-7
14. Harlow E, Whyte P, Franza BR, Jr., Schley C. Association of adenovirus early-region 1A proteins with cellular polypeptides. Molecular & Cellular Biology 1986; 6:1579-89; PMID:2431282
15. Yee SP, Branton PE. Detection of cellular proteins associated with human adenovirus type 5 early region 1A polypeptides. Virology 1985; 147:142-53; PMID:2932846; http://dx.doi.org/10.1016/0042-6822(85)90234-X
16. Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989; 243:934-7; PMID:2537532; http://dx.doi.org/10.1126/science.2537532
17. Munger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO Journal 1989; 8:4099-105; PMID:2556261
18. Lee JO, Russo AA, Pavletich NP. Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. Nature 1998; 391:859-65; PMID:9495340; http://dx.doi.org/10.1038/36038
19. Morris EJ, Dyson NJ. Retinoblastoma protein partners. Adv Cancer Res 2001; 82:1-54; PMID:11447760; http://dx.doi.org/10.1016/S0065-230X(01)82001-7
20. Woo MS, Sanchez I, Dynlacht BD. p130 and p107 use a conserved domain to inhibit cellular cyclindependent kinase activity. Mol Cell Biol 1997; 17:3566-79; PMID:9199292
21. Castano E, Kleyner Y, Dynlacht BD. Dual cyclinbinding domains are required for p107 to function as a kinase inhibitor. Mol Cell Biol 1998; 18:5380-91; PMID:9710622
22. Pan W, Cox S, Hoess RH, Grafstrom RH. A cyclin D1/cyclin-dependent kinase 4 binding site within the C domain of the retinoblastoma protein. Cancer Res 2001; 61:2885-91; PMID:11306463
23. Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, Taya Y, Kaelin WG Jr Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol Cell Biol 1999; 19:1068-80; PMID:9891042
24. Mayol X, Garriga J, Graña X. Cell cycle-dependent phosphorylation of the retinoblastoma-related protein p130. Oncogene 1995; 11:801-8; PMID:7651744
25. Mayol X, Garriga J, Graña X. G1 cyclin/CDK-independent phosphorylation and accumulation of p130 during the transition from G1 to G0 lead to its association with E2F-4. Oncogene 1996; 13:237-46; PMID:8710362
26. Smith EJ, Leone G, Degregori J, Jakoi L, Nevins JR. The accumulation of an E2F-p130 transcriptional repressor distinguishes a G(0) cell state from a G(1) cell state. Molecular & Cellular Biology 1996; 16:6965-76; PMID:8943352
27. Bhattacharya S, Garriga J, Calbo J, Yong T, Haines DS, Graña X. SKP2 associates with p130 and accelerates p130 ubiquitylation and degradation in human cells. Oncogene 2003; 22:2443-51; PMID:12717421; http://dx.doi.org/10.1038/sj.onc.1206339
28. Tedesco D, Lukas J, Reed SI. The pRb-related protein p130 is regulated by phosphorylation-dependent proteolysis via the protein-ubiquitin ligase SCF(Skp2). Genes Dev 2002; 16:2946-57; PMID:12435635; http://dx.doi.org/10.1101/gad.1011202
29. Zhu L, Xie E, Chang LS. Differential roles of two tandem E2F sites in repression of the human p107 promoter by retinoblastoma and p107 proteins. Molecular & Cellular Biology 1995; 15:3552-62; PMID:7791762
30. Beijersbergen RL, Carlee L, Kerkhoven RM, Bernards R. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes. Genes & Development 1995; 9:1340-53; PMID:7797074; http://dx.doi.org/10.1101/gad.9.11.1340
31. Henley SA, Dick FA. The retinoblastoma family of proteins and their regulatory functions in the mammalian cell division cycle. Cell Div 2012; 7:10; PMID:22417103; http://dx.doi.org/10.1186/1747-1028-7-10
32. Zhang HS, Postigo AA, Dean DC. Active transcriptional repression by the Rb-E2F complex mediates G1 arrest triggered by p16INK4a, TGFbeta, and contact inhibition. Cell 1999; 97:53-61; PMID:10199402; http://dx.doi.org/10.1016/S0092-8674(00)80714-X
33. Hurford RK, Jr., Cobrinik D, Lee MH, Dyson N. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev 1997; 11:1447-63; PMID:9192872; http://dx.doi.org/10.1101/gad.11.11.1447
34. Balciunaite E, Spektor A, Lents NH, Cam H, Te Riele H, Scime A, Rudnicki MA, Young R, Dynlacht BD. Pocket protein complexes are recruited to distinct targets in quiescent and proliferating cells. Mol Cell Biol 2005; 25:8166-78; PMID:16135806; http://dx.doi.org/10.1128/MCB.25.18.8166-8178.2005
35. Rowland BD, Bernards R. Re-evaluating cell-cycle regulation by E2Fs. Cell 2006; 127:871-4; PMID:17129771; http://dx.doi.org/10.1016/j.cell.2006.11.019
36. Bertoli C, Skotheim JM, de Bruin RA. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 2013; 14:518-28; PMID:23877564; http://dx.doi.org/10.1038/nrm3629
37. Calbo J, Parreno M, Sotillo E, Yong T, Mazo A, Garriga J, Graña X. G1 cyclin/cyclin-dependent kinasecoordinated phosphorylation of endogenous pocket proteins differentially regulates their interactions with E2F4 and E2F1 and gene expression. J Biol Chem 2002; 277:50263-74; PMID:12401786; http://dx.doi.org/10.1074/jbc.M209181200
38. Lee EY, Cam H, Ziebold U, Rayman JB, Lees JA, Dynlacht BD. E2F4 loss suppresses tumorigenesis in Rb mutant mice. Cancer Cell 2002; 2:463-72; PMID:12498715; http://dx.doi.org/10.1016/S1535-6108(02)00207-6
39. Kurimchak A, Haines DS, Garriga J, Wu S, De Luca F, Sweredoski MJ, Deshaies RJ, Hess S, Graña X. Activation of p107 by fibroblast growth factor, which is essential for chondrocyte cell cycle exit, is mediated by the protein phosphatase 2A/B55alpha holoenzyme. Mol Cell Biol 2013; 33:3330-42; PMID:23775125; http://dx.doi.org/10.1128/MCB.00082-13
40. Gaubatz S, Lees JA, Lindeman GJ, Livingston DM. E2F4 is exported from the nucleus in a CRM1-dependent manner. Mol Cell Biol 2001; 21:1384-92; PMID:11158323; http://dx.doi.org/10.1128/MCB.21.4.1384-1392.2001
41. Gaubatz S, Lindeman GJ, Ishida S, Jakoi L, Nevins JR, Livingston DM, Rempel RE. E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell 2000; 6:729-35; PMID:11030352; http://dx.doi.org/10.1016/S1097-2765(00)00071-X
42. Kurimchak A, Graña X. PP2A holoenzymes negatively and positively regulate cell cycle progression by dephosphorylating pocket proteins and multiple CDK substrates. Gene 2012; 499:1-7; PMID:22387205; http://dx.doi.org/10.1016/j.gene.2012.02.015
43. Ludlow JW, Glendening CL, Livingston DM, DeCarprio JA. Specific enzymatic dephosphorylation of the retinoblastoma protein. Molecular & Cellular Biology 1993; 13:367-72; PMID:8380224
44. Durfee T, Becherer K, Chen PL, Yeh SH, Yang Y, Kilburn AE, Lee WH, Elledge SJ. The retinoblastoma protein associates with the protein phosphatase type 1 catalytic subunit. Genes & Development 1993; 7:555-69; PMID:8384581; http://dx.doi.org/10.1101/gad.7.4.555
45. Nelson DA, Ludlow JW. Characterization of the mitotic phase pRb-directed protein phosphatase activity. Oncogene 1997; 14:2407-15; PMID:9188855; http://dx.doi.org/10.1038/sj.onc.1201081
46. Nelson DA, Krucher NA, Ludlow JW. High molecular weight protein phosphatase type 1 dephosphorylates the retinoblastoma protein. J Biol Chem 1997; 272:4528-35; PMID:9020179; http://dx.doi.org/10.1074/jbc.272.7.4528
47. Dunaief JL, King A, Esumi N, Eagen M, Dentchev T, Sung CH, Chen S, Zack DJ. Protein Phosphatase 1 binds strongly to the retinoblastoma protein but not to p107 or p130 in vitro and in vivo. Curr Eye Res 2002; 24:392-6; PMID:12434308; http://dx.doi.org/10.1076/ceyr.24.5.392.8524
48. Cicchillitti L, Fasanaro P, Biglioli P, Capogrossi MC, Martelli F. Oxidative stress induces protein phosphatase 2A-dependent dephosphorylation of the pocket proteins pRb, p107, and p130. J Biol Chem 2003; 278:19509-17; PMID:12621062; http://dx.doi.org/10.1074/jbc.M300511200
49. Voorhoeve PM, Hijmans EM, Bernards R. Functional interaction between a novel protein phosphatase 2A regulatory subunit, PR59, and the retinoblastomarelated p107 protein. Oncogene 1999; 18:515-24; PMID:9927208; http://dx.doi.org/10.1038/sj.onc.1202316
50. Vuocolo SC, Purev E, Zhang D, Bartek J, Hansen K, Soprano DR, Soprano KJ. Protein phosphatase 2A associates with Rb2/p130 and mediates retinoic acid induced growth suppression of ovariancarcinoma cells. J Biol Chem 2003; 278(43):41881-9; PMID:12915404
51. Voorhoeve PM, Watson RJ, Farlie PG, Bernards R, Lam EW. Rapid dephosphorylation of p107 following UV irradiation. Oncogene 1999; 18:679-88; PMID:9989818; http://dx.doi.org/10.1038/sj.onc.1202289
52. Garriga J, Jayaraman AL, Limon A, Jayadeva G, Sotillo E, Truongcao M, Patsialou A, Wadzinski BE, Graña X. A Dynamic Equilibrium Between CDKs and PP2A Modulates Phosphorylation of pRB, p107 and p130. Cell Cycle 2004; 3:(10):1320-30; PMID:15467457
53. Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 2008.
54. Kurimchak A, Graña X. PP2A Counterbalances Phosphorylation of pRB and Mitotic Proteins by Multiple CDKs: Potential Implications for PP2A Disruption in Cancer. Genes Cancer 2013; 3:739-48; PMID:23634261; http://dx.doi.org/10.1177/1947601912473479
55. Stone SR, Hofsteenge J, Hemmings BA. Molecular cloning of cDNAs encoding two isoforms of the catalytic subunit of protein phosphatase 2A. Biochemistry 1987; 26:7215-20; PMID:2827745; http://dx.doi.org/10.1021/bi00397a003
56. Gotz J, Probst A, Ehler E, Hemmings B, Kues W. Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Calpha. Proc Natl Acad Sci U S A 1998; 95:12370-5; PMID:9770493; http://dx.doi.org/10.1073/pnas.95.21.12370
57. Ogris E, Gibson DM, Pallas DC. Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen. Oncogene 1997; 15:911-7; PMID:9285686; http://dx.doi.org/10.1038/sj.onc.1201259
58. Chen J, Martin BL, Brautigan DL. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science 1992; 257:1261-4; PMID:1325671; http://dx.doi.org/10.1126/science.1325671
59. Longin S, Zwaenepoel K, Louis JV, Dilworth S, Goris J, Janssens V. Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic Subunit. J Biol Chem 2007; 282:26971-80; PMID:17635907; http://dx.doi.org/10.1074/jbc.M704059200
60. Lee J, Stock J. Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase. J Biol Chem 1993; 268:19192-5; PMID:8396127
61. Guo H, Damuni Z. Autophosphorylation-activated protein kinase phosphorylates and inactivates protein phosphatase 2A. Proc Natl Acad Sci U S A 1993; 90:2500-4; PMID:7681598; http://dx.doi.org/10.1073/pnas.90.6.2500
62. Ogris E, Du X, Nelson KC, Mak EK, Yu XX, Lane WS, Pallas DC. A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. J Biol Chem 1999; 274:14382-91; PMID:10318862; http://dx.doi.org/10.1074/jbc.274.20.14382
63. Lee J, Chen Y, Tolstykh T, Stock J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc Natl Acad Sci U S A 1996; 93:6043-7; PMID:8650216; http://dx.doi.org/10.1073/pnas.93.12.6043
64. Cayla X, Van Hoof C, Bosch M, Waelkens E, Vandekerckhove J, Peeters B, Merlevede W, Goris J. Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. J Biol Chem 1994; 269:15668-75; PMID:8195217
65. Xing Y, Li Z, Chen Y, Stock JB, Jeffrey PD, Shi Y. Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell 2008; 133:154-63; PMID:18394995; http://dx.doi.org/10.1016/j.cell.2008.02.041
66. Longin S, Jordens J, Martens E, Stevens I, Janssens V, Rondelez E, De Baere I, Derua R, Waelkens E, Goris J, Van Hoof C. An inactive protein phosphatase 2A population is associated with methylesterase and can be re-activated by the phosphotyrosyl phosphatase activator. Biochem J 2004; 380:111-9; PMID:14748741; http://dx.doi.org/10.1042/BJ20031643
67. Jordens J, Janssens V, Longin S, Stevens I, Martens E, Bultynck G, Engelborghs Y, Lescrinier E, Waelkens E, Goris J, Van Hoof C. The protein phosphatase 2A phosphatase activator is a novel peptidyL-prolyl cis/trans-isomerase. J Biol Chem 2006; 281:6349-57; PMID:16380387; http://dx.doi.org/10.1074/jbc.M507760200
68. Tolstykh T, Lee J, Vafai S, Stock JB. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits. Embo j 2000; 19:5682-91; PMID:11060019; http://dx.doi.org/10.1093/emboj/19.21.5682
69. Bryant JC, Westphal RS, Wadzinski BE. Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit. Biochem J 1999; 339(Pt 2):241-6; PMID:10191253; http://dx.doi.org/10.1042/0264-6021:3390241
70. Yu XX, Du X, Moreno CS, Green RE, Ogris E, Feng Q, Chou L, McQuoid MJ, Pallas DC. Methylation of the protein phosphatase 2A catalytic subunit is essential for association of Balpha regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen. Mol Biol Cell 2001; 12:185-99; PMID:11160832; http://dx.doi.org/10.1091/mbc.12.1.185
71. Ikehara T, Ikehara S, Imamura S, Shinjo F, Yasumoto T. Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for the catalytic activity and the binding of regulatory subunit (PR55/B). Biochem Biophys Res Commun 2007; 354:1052-7; PMID:17274953; http://dx.doi.org/10.1016/j.bbrc.2007.01.085
72. Shi Y. Serine/threonine phosphatases: mechanism through structure. Cell 2009; 139:468-84; PMID:19879837; http://dx.doi.org/10.1016/j.cell.2009.10.006
73. Hemmings BA, Adams-Pearson C, Maurer F, Muller P, Goris J, Merlevede W, Hofsteenge J, Stone SR. αand β-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry 1990; 29:3166-73; PMID:2159327; http://dx.doi.org/10.1021/bi00465a002
74. Zhou J, Pham HT, Ruediger R, Walter G. Characterization of the Aalpha and Abeta subunit isoforms of protein phosphatase 2A: differences in expression, subunit interaction, and evolution. Biochem J 2003; 369:387-98; PMID:12370081; http://dx.doi.org/10.1042/BJ20021244
75. Groves MR, Hanlon N, Turowski P, Hemmings BA, Barford D. The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell 1999; 96:99-110; PMID:9989501; http://dx.doi.org/10.1016/S0092-8674(00)80963-0
76. Cho US, Xu W. Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 2007; 445:53-7; PMID:17086192; http://dx.doi.org/10.1038/nature05351
77. Xu Y, Chen Y, Zhang P, Jeffrey PD, Shi Y. Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. Mol Cell 2008; 31:873-85; PMID:18922469; http://dx.doi.org/10.1016/j.molcel.2008.08.006
78. 2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation. Cell Res 2013; 23:931-46; PMID:23752926; http://dx.doi.org/10.1038/cr.2013.77
79. Xu Y, Xing Y, Chen Y, Chao Y, Lin Z, Fan E, Yu JW, Strack S, Jeffrey PD, Shi Y. Structure of the protein phosphatase 2A holoenzyme. Cell 2006; 127:1239-51; PMID:17174897; http://dx.doi.org/10.1016/j.cell.2006.11.033
80. Virshup DM, Shenolikar S. From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 2009; 33:537-45; PMID:19285938; http://dx.doi.org/10.1016/j.molcel.2009.02.015
81. Xing Y, Xu Y, Chen Y, Jeffrey PD, Chao Y, Lin Z, Li Z, Strack S, Stock JB, Shi Y. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 2006; 127:341-53; PMID:17055435; http://dx.doi.org/10.1016/j.cell.2006.09.025
82. Jayadeva G, Kurimchak A, Garriga J, Sotillo E, Davis AJ, Haines DS, Mumby M, Graña X. B55alpha PP2A holoenzymes modulate the phosphorylation status of the retinoblastoma-related protein p107 and its activation. J Biol Chem 2010; 285:29863-73; PMID:20663872; http://dx.doi.org/10.1074/jbc.M110.162354
83. Yang J, Phiel C. Functions of B56-containing PP2As in major developmental and cancer signaling pathways. Life Sci 2010; 87:659-66; PMID:20934435; http://dx.doi.org/10.1016/j.lfs.2010.10.003
84. Saraf A, Oberg EA, Strack S. Molecular determinants for PP2A substrate specificity: charged residues mediate dephosphorylation of tyrosine hydroxylase by the PP2A/B' regulatory subunit. Biochemistry 2010; 49:986-95; PMID:20017541; http://dx.doi.org/10.1021/bi902160t
85. 2+-binding EF-hand motifs in the B"/PR72 subunit of protein phosphatase 2A. J Biol Chem 2003; 278:10697-706; PMID:12524438; http://dx.doi.org/10.1074/jbc.M211717200
86. Hendrix P, Mayer-Jackel RE, Cron P, Goris J, Hofsteenge J, Merlevede W, Hemmings BA. Structure and expression of a 72-kDa regulatory subunit of protein phosphatase 2A. Evidence for different size forms produced by alternative splicing. J Biol Chem 1993; 268:15267-76; PMID:8392071
87. Yan Z, Fedorov SA, Mumby MC, Williams RS. PR48, a novel regulatory subunit of protein phosphatase 2A, interacts with Cdc6 and modulates DNA replication in human cells. Mol Cell Biol 2000; 20:1021-9; PMID:10629059; http://dx.doi.org/10.1128/MCB.20.3.1021-1029.2000
88. Davis AJ, Yan Z, Martinez B, Mumby MC. Protein phosphatase 2A is targeted to cell division control protein 6 by a calcium-binding regulatory subunit. J Biol Chem 2008; 283:16104-14; PMID:18397887; http://dx.doi.org/10.1074/jbc.M710313200
89. Magenta A, Fasanaro P, Romani S, Di Stefano V, Capogrossi MC, Martelli F. Protein phosphatase 2A subunit PR70 interacts with pRb and mediates its dephosphorylation. Mol Cell Biol 2008; 28:873-82; PMID:17991896; http://dx.doi.org/10.1128/MCB.00480-07
90. Moreno CS, Park S, Nelson K, Ashby D, Hubalek F, Lane WS, Pallas DC. WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A. J Biol Chem 2000; 275:5257-63; PMID:10681496; http://dx.doi.org/10.1074/jbc.275.8.5257
91. Goudreault M, D'Ambrosio LM, Kean MJ, Mullin MJ, Larsen BG, Sanchez A, Chaudhry S, Chen GI, Sicheri F, Nesvizhskii AI, Aebersold R, Raught B, Gingras AC. A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein. Mol Cell Proteomics 2009; 8:157-71; PMID:18782753; http://dx.doi.org/10.1074/mcp.M800266-MCP200
92. Hwang J, Pallas DC. STRIPAK complexes: structure, biological function, and involvement in human diseases. Int J Biochem Cell Biol 2014; 47:118-48; PMID:24333164; http://dx.doi.org/10.1016/j.biocel.2013.11.021
93. Ory S, Zhou M, Conrads TP, Veenstra TD, Morrison DK. Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr Biol 2003; 13:1356-64; PMID:12932319
94. Hirschi A, Cecchini M, Steinhardt RC, Schamber MR, Dick FA, Rubin SM. An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein. Nat Struct Mol Biol 2010; 17:1051-7; PMID:20694007; http://dx.doi.org/10.1038/nsmb.1868
95. Purev E, Giordano A, Soprano DR, Soprano KJ. Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth. J Cell Physiol 2006; 206:495-502; PMID:16206244; http://dx.doi.org/10.1002/jcp.20490
96. Purev E, Soprano DR, Soprano KJ. PP2A interaction with Rb2/p130 mediates translocation of Rb2/p130 into the nucleus in all-trans retinoic acid-treated ovarian carcinoma cells. J Cell Physiol 2011; 226:1027-34; PMID:20857408; http://dx.doi.org/10.1002/jcp.22418
97. Chen CR, Kang Y, Siegel PM, Massague J. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 2002; 110:19-32; PMID:12150994; http://dx.doi.org/10.1016/S0092-8674(02)00801-2
98. Griswold-Prenner I, Kamibayashi C, Maruoka EM, Mumby MC, Derynck R. Physical and functional interactions between type I transforming growth factor b receptors and Balpha, a WD-40 repeat subunit of phosphatase 2A. Mol Cell Biol 1998; 18:6595-604; PMID:9774674
99. Bengtsson L, Schwappacher R, Roth M, Boergermann JH, Hassel S, Knaus P. PP2A regulates BMP signalling by interacting with BMP receptor complexes and by dephosphorylating both the C-terminus and the linker region of Smad1. J Cell Sci 2009; 122:1248-57; PMID:19339557; http://dx.doi.org/10.1242/jcs.039552
100. Kolupaeva V, Laplantine E, Basilico C. PP2A-mediated dephosphorylation of p107 plays a critical role in chondrocyte cell cycle arrest by FGF. PLoS One 2008; 3:e3447; PMID:18927618
101. Dailey L, Laplantine E, Priore R, Basilico C. A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation. J Cell Biol 2003; 161:1053-66; PMID:12821644; http://dx.doi.org/10.1083/jcb.200302075
102. Cobrinik D, Lee MH, Hannon G, Mulligan G, Bronson RT, Dyson N, Harlow E, Beach D, Weinberg RA, Jacks T. Shared role of the pRb-related p130 and p107 proteins in limb development. Genes & Development 1996; 10:1633-44; PMID:8682294; http://dx.doi.org/10.1101/gad.10.13.1633
103. Laplantine E, Rossi F, Sahni M, Basilico C, Cobrinik D. FGF signaling targets the pRb-related p107 and p130 proteins to induce chondrocyte growth arrest. J Cell Biol 2002; 158:741-50; PMID:12177046; http://dx.doi.org/10.1083/jcb.200205025
104. Lee MH, Williams BO, Mulligan G, Mukai S, Bronson RT, Dyson N, Jacks T Targeted disruption of p107: functional overlap between p107 and Rb. Genes & Development 1996; 10:1621-32; PMID:8682293; http://dx.doi.org/10.1101/gad.10.13.1621
105. Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 2002; 16:1446-65; PMID:12080084; http://dx.doi.org/10.1101/gad.990702
106. Wuelling M, Vortkamp A. Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification. Pediatr Nephrol 2010; 25:625-31; PMID:19949815; http://dx.doi.org/10.1007/s00467-009-1368-6
107. Mukhopadhyay K, Lefebvre V, Zhou G, Garofalo S, Kimura JH, de Crombrugghe B. Use of a new rat chondrosarcoma cell line to delineate a 119-base pair chondrocyte-specific enhancer element and to define active promoter segments in the mouse pro-a 1(II) collagen gene. J Biol Chem 1995; 270:27711-9; PMID:7499238
108. Krejci P, Bryja V, Pachernik J, Hampl A, Pogue R, Mekikian P, Wilcox WR. FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells. Exp Cell Res 2004; 297:152-64; PMID:15194433; http://dx.doi.org/10.1016/j.yexcr.2004.03.011
109. Raucci A, Laplantine E, Mansukhani A, Basilico C. Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes. J Biol Chem 2004; 279:1747-56; PMID:14593093; http://dx.doi.org/10.1074/jbc.M310384200
110. Priore R, Dailey L, Basilico C. Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes. J Cell Physiol 2006; 207:800-8; PMID:16523491; http://dx.doi.org/10.1002/jcp.20620
111. Yeh N, Miller JP, Gaur T, Capellini TD, Nikolich- Zugich J, de la Hoz C, Selleri L, Bromage TG, van Wijnen AJ, Stein GS, Lian JB, Vidal A, Koff A. Cooperation between p27 and p107 during endochondral ossification suggests a genetic pathway controlled by p27 and p130. Mol Cell Biol 2007; 27:5161-71; PMID:17502351; http://dx.doi.org/10.1128/MCB.02431-06
112. Yan YM, Lee MH, Massague J, Barbacid M. Ablation Of the Cdk Inhibitor P57(Kip2) Results In Increased Apoptosis and Delayed Differentiation During Mouse Development. Genes & Dev 1997; 11:973-83; PMID:9136926; http://dx.doi.org/10.1101/gad.11.8.973
113. Aikawa T, Segre GV, Lee K. Fibroblast growth factor inhibits chondrocytic growth through induction of p21 and subsequent inactivation of cyclin E-Cdk2. J Biol Chem 2001; 276:29347-52; PMID:11384971; http://dx.doi.org/10.1074/jbc.M101859200
114. Kolupaeva V, Daempfling L, Basilico C. The B55alpha regulatory subunit of protein phosphatase 2A mediates fibroblast growth factor-induced p107 dephosphorylation and growth arrest in chondrocytes. Mol Cell Biol 2013; 33:2865-78; PMID:23716589; http://dx.doi.org/10.1128/MCB.01730-12
115. Schmitz MH, Held M, Janssens V, Hutchins JR, Hudecz O, Ivanova E, Goris J, Trinkle-Mulcahy L, Lamond AI, Poser I, et al. Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells. Nat Cell Biol 2009; 12:886-93; PMID:20711181; http://dx.doi.org/10.1038/ncb20
116. Adams DG, Coffee RL, Jr., Zhang H, Pelech S, Strack S, Wadzinski BE. Positive regulation of Raf1-MEK1/2-ERK1/2 signaling by protein serine/threonine phosphatase 2A holoenzymes. J Biol Chem 2005; 280:42644-54; PMID:16239230; http://dx.doi.org/10.1074/jbc.M502464200
117. Sadasivam S, DeCaprio JA. The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat Rev Cancer 2013; 13:585-95; PMID:23842645; http://dx.doi.org/10.1038/nrc3556
118. Litovchick L, Sadasivam S, Florens L, Zhu X, Swanson SK, Velmurugan S, Chen R, Washburn MP, Liu XS, DeCaprio JA. Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Mol Cell 2007; 26:539-51; PMID:17531812; http://dx.doi.org/10.1016/j.molcel.2007.04.015
119. Pilkinton M, Sandoval R, Colamonici OR. Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cyclephase-dependent context distinct from the Drosophila dREAM complex. Oncogene 2007; 26:7535-43; PMID:17563750; http://dx.doi.org/10.1038/sj.onc.1210562
120. Sadasivam S, Duan S, DeCaprio JA. The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev 2012; 26:474-89; PMID:22391450; http://dx.doi.org/10.1101/gad.181933.111
121. Litovchick L, Florens LA, Swanson SK, Washburn MP, DeCaprio JA. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev 2011; 25:801-13; PMID:21498570; http://dx.doi.org/10.1101/gad.2034211
122. Forristal C, Henley SA, Macdonald JI, Bush JR, Ort C, Passos DT, Talluri S, Ishak CA, Thwaites MJ, Norley CJ, et al. Loss of the mammalian DREAM complex deregulates chondrocyte proliferation. Mol Cell Biol 2014; 34(12):2221-34; PMID:24710275; http://dx.doi.org/10.1128/MCB.01523-13
123. Avni D, Yang H, Martelli F, Hofmann F, ElShamy WM, Ganesan S,Scully R, Livingston DM. Active localization of the retinoblastoma protein in chromatin and its response to S phase DNA damage. Mol Cell 2003; 12:735-46; PMID:14527418; http://dx.doi.org/10.1016/S1097-2765(03)00355-1
124. Lorca T, Castro A. Deciphering the New Role of the Greatwall/PP2A Pathway in Cell Cycle Control. Genes Cancer 2012; 3:712-20; PMID:23634258; http://dx.doi.org/10.1177/1947601912473478
125. Lorca T, Castro A. The Greatwall kinase: a new pathway in the control of the cell cycle. Oncogene 2012; PMID:22469975