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


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].


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