Pathway maps

Cell cycle_Role of 14-3-3 proteins in cell cycle regulation
Cell cycle_Role of 14-3-3 proteins in cell cycle regulation

Object List (links open in MetaCore):

14-3-3 gamma, 14-3-3 epsilon, ATR, HUS1, Chk2, CDC25A, ATM, p53, AKT(PKB), MAPKAPK2, 14-3-3 sigma, CDK1 (p34), 14-3-3 zeta/delta, 14-3-3 beta/alpha, TAK1(MAP3K7), 14-3-3 eta, CDC25B, p38 MAPK, Chk1, 14-3-3 tau, CDC25C, Wee1

Description

Role of 14-3-3 proteins in cell cycle regulation

The 14-3-3 s are a family of highly conserved proteins that play important roles in a wide range of cellular processes including signal transduction, apoptosis, cell cycle progression, and checkpoint activation within all eukaryotic cells. These 28-33 kDa helical proteins include nine isotypes ( 14-3-3 alpha, 14-3-3 beta, 14-3-3 gamma, 14-3-3 delta, 14-3-3 epsilon, 14-3-3 eta, 14-3-3 sigma, 14-3-3 tau and 14-3-3 zeta, with 14-3-3 alpha and 14-3-3 delta being phosphorylated forms of 14-3-3 beta and 14-3-3 zeta, respectively) in mammals.

14-3-3 proteins regulate the cell cycle and prevent apoptosis by controlling the nuclear and cytoplasmic distribution of signaling molecules with which they interact. 14-3-3 proteins have crucial functions during undisturbed cell divisions and several mechanisms involving 14-3-3 -ligand association ensure that mitosis is not prematurely activated before the completion of DNA replication in interphase [1].

14-3-3 proteins regulate the cell cycle via cell cycle checkpoint kinase 1 ( Chk1 ) [2], and by phosphorylation of cell division cycle 25 phosphatases ( CDC25 s) [3], [4], tyrosine kinase Wee1 [5], [6], tumor suppressor p53 [7] and cyclin-dependent kinase 1 ( CDK1 ) [8].

CDC25 s are a main target for 14-3-3 -regulation. CDC25 s activate CDK s by dephosphorylation, thus stimulating cell cycle progression . Different CDC25 s participate in different phases of cell cycle. CDC25A takes part in regulation of G1/S transition, whereas CDC25B and CDC25C regulate G2/M transition. Lack of active CDC25 s results in the accumulation of the phosphorylated (inactive) forms of CDK s, which are incapable to participate in initiation of replication [9].

CDC25 s may be phosphorylated via ataxia telangiectasia mutated serine-protein kinase ( ATM )/ Chk s and ataxia telangiectasia and Rad3 related protein kinase ( ATR )/ Chk1 pathways. Chk1 is activated by 14-3-3 zeta/delta with help of the checkpoint protein HUS1 [2]. In addition, mitogen-activated protein kinase p38/ mitogen-activated protein kinase-activated protein kinase 2 ( MAPKAPK2 ) pathway [10] and mitogen-activated protein kinase kinase kinase 7 ( TAK1 ) [11] may participate in phosphorylation of CDC25B and CDC25C, as well.

Various isotypes of 14-3-3 proteins inhibit phosphorylated CDC25 s, which probably results in the retention of CDC25 s in the cytoplasm [4] and/or the blocked access of CDK s to the catalytic site of CDC25 s [3]. Once mitosis is activated, cytoplasmic sequestration of CDC25C by 14-3-3 proteins is inhibited by a CDK1 -mediated phosphorylation [12].

In addition, CDK1 is regulated by 14-3-3 proteins directly (by 14-3-3 sigma [8] ) or via Wee1. Active Wee1 inhibits Cdk1 by Tyr15 phosphorylation. Wee1 may be activated by 14-3-3 alpha/beta [13] and 14-3-3 delta/zeta [6] isotypes. On the other hand, Wee1 phosphorylated by protein kinase B ( AKT ) on Ser-642 may be retained in the cytoplasm by 14-3-3 eta [5].

It was shown that some isotypes of 14-3-3 proteins ( 14-3-3 gamma, 14-3-3 tau, 14-3-3 epsilon [7] and 14-3-3 sigma [14] ) may activates p53. Ionizing radiation-induced dephosphorylation of p53 on Ser-376 is necessary for this process [7].

References:

  1. Brunet A, Kanai F, Stehn J, Xu J, Sarbassova D, Frangioni JV, Dalal SN, DeCaprio JA, Greenberg ME, Yaffe MB
    14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. The Journal of cell biology 2002 Mar 4;156(5):817-28
  2. Jiang K, Pereira E, Maxfield M, Russell B, Goudelock DM, Sanchez Y
    Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345. The Journal of biological chemistry 2003 Jul 4;278(27):25207-17
  3. Forrest A, Gabrielli B
    Cdc25B activity is regulated by 14-3-3. Oncogene 2001 Jul 19;20(32):4393-401
  4. Dalal SN, Yaffe MB, DeCaprio JA
    14-3-3 family members act coordinately to regulate mitotic progression. Cell cycle (Georgetown, Tex.) 2004 May;3(5):672-7
  5. Katayama K, Fujita N, Tsuruo T
    Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Molecular and cellular biology 2005 Jul;25(13):5725-37
  6. Rothblum-Oviatt CJ, Ryan CE, Piwnica-Worms H
    14-3-3 binding regulates catalytic activity of human Wee1 kinase. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 2001 Dec;12(12):581-9
  7. Stavridi ES, Chehab NH, Malikzay A, Halazonetis TD
    Substitutions that compromise the ionizing radiation-induced association of p53 with 14-3-3 proteins also compromise the ability of p53 to induce cell cycle arrest. Cancer research 2001 Oct 1;61(19):7030-3
  8. Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel JT, McShea A, Hermeking H, Funk JO
    The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax. The Journal of biological chemistry 2001 Nov 30;276(48):45201-6
  9. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S
    Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual review of biochemistry 2004;73:39-85
  10. Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AE, Yaffe MB
    MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Molecular cell 2005 Jan 7;17(1):37-48
  11. Peng CY, Graves PR, Ogg S, Thoma RS, Byrnes MJ 3rd, Wu Z, Stephenson MT, Piwnica-Worms H
    C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 1998 Mar;9(3):197-208
  12. Bulavin DV, Higashimoto Y, Demidenko ZN, Meek S, Graves P, Phillips C, Zhao H, Moody SA, Appella E, Piwnica-Worms H, Fornace AJ Jr
    Dual phosphorylation controls Cdc25 phosphatases and mitotic entry. Nature cell biology 2003 Jun;5(6):545-51
  13. Wang Y, Jacobs C, Hook KE, Duan H, Booher RN, Sun Y
    Binding of 14-3-3beta to the carboxyl terminus of Wee1 increases Wee1 stability, kinase activity, and G2-M cell population. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 2000 Apr;11(4):211-9
  14. Mhawech P
    14-3-3 proteins--an update. Cell research 2005 Apr;15(4):228-36