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

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

The 14-3-3s 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 (CDC25s) [3], [4], tyrosine kinase Wee1 [5], [6], tumor suppressor p53 [7] and cyclin-dependent kinase 1 (CDK1) [8].

CDC25s are a main target for 14-3-3-regulation. CDC25s activate CDKs by dephosphorylation, thus stimulating cell cycle progression. Different CDC25s 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 CDC25s results in the accumulation of the phosphorylated (inactive) forms of CDKs, which are incapable to participate in initiation of replication [9].

CDC25s may be phosphorylated via ataxia telangiectasia mutated serine-protein kinase (ATM)/ Chks 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 CDC25s, which probably results in the retention of CDC25s in the cytoplasm [4] and/or the blocked access of CDKs to the catalytic site of CDC25s [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:

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