Landscape of Pin1 in the cell cycle

Abstract

Pin1 is a peptidyl-prolyl isomerase which plays a critical role in many diseases including cancer and Alzheimer's disease. The essential role of Pin1 is to affect stability, localization or function of phosphoproteins by catalyzing structural changes. Among the collection of Pin1 substrates, many have been shown to be involved in regulating cell cycle progression. The cell cycle disorder caused by dysregulation of these substrates is believed to be a common phenomenon in cancer. A number of recent studies have revealed possible functions of several important Pin1-binding cell cycle regulators. Investigating the involvement of Pin1 in the cell cycle may assist in the development of future cancer therapeutics. In this review, we summarize current knowledge regarding the network of Pin1 substrates and Pin1 regulators in cell cycle progression. In G1/S progression, cyclin D1, RB, p53, p27, and cyclin E are all well-known cell cycle regulators that are modulated by Pin1. During G2/M transition, our lab has shown that Aurora A suppresses Pin1 activity through phosphorylation at Ser16 and cooperates with hBora to modulate G2/M transition. We conclude that Pin1 may be thought of as a molecular timer which modulates cell cycle progression networks.

Keywords: Aurora A; Pin1; cell cycle; hBora.

Figure 1

Pin1 regulating network in cell cycle. During G1/S phase, Pin1 promotes cyclin D1 overexpression and RB phosphorylation. The phosphorylated RB releases E2F, which is a transcriptional factor to enhance Pin1 expression. Pin1 stimulates cyclin E degradation in S phase. During G2 phase, Aurora A inactive Pin1 and active PLK result in CDC25 activation triggers G2/M transition. During the G2/M transition, GSK-3β interacts with and phosphorylates hBora at S274/S278, and in the meantime, Aurora A interacts with and phosphorylates Pin1 at Ser16 to disrupt Pin1 function by suppressing Pin1 binding to phospho-hBora and thus preventing β-TrCP-mediated premature hBora degradation. Therefore, Aurora A forms a complex with phospho-hBora to phosphorylate Plk1 at Thr210 and activates Plk1. Plk1 activates CDC25 result in the activation of the Cyclin-B1/CDK1 complex and promotes mitotic entry. After mitotic entry, Pin1 could recover the binding activity and enhance protein stability through PP2A and PLK1. The active Pin1 promotes the degradation of hBora. Aurora A is then available to bind with TPX2 result in mitotic spindle assembly. Wee1 is phosphorylated at Tyr168 by CDK1 and Pin1 isomerize phosphorylated Wee1 inactivation.