Ying Tong*, Yuhuang Li and Zhi-Xiong Xiao
Center of Growth, Metabolism and Aging, Key Laboratory of Biological Resources and Ecological Environment of Ministry of Education, College of Life Sciences and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, P.R. China
Received date: June 07, 2017; Accepted date: June 16, 2017; Published date: June 26, 2017
Citation: Tong Y, Li Y, Xiao ZX (2017) Proline Isomerase Pin1 is a critical Regulator for Retinoblastoma Protein Phosphorylation in Control of Cell Cycle and S-phase Check-point Upon DNA Damage. J Cell Signal 2:157.
Copyright: © 2017 Tong Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Protein phosphorylation represents an universal regulatory mechanism in cellular signalling. Pin1-catalyzed isomerization of phospho-protein plays a pivotal role in this regulatory network. Through binding to specific phosphorylated Ser/Thr-Pro bonds, Pin1 induces conformational change of its targets, therefore affecting many diverse cellular events. Reports from us and others demonstrate that Pin1 can activate cyclin D1, resulting in hyperphosphorylation of Rb and facilitating G1-S transition. Meanwhile, Pin1 can directly bind to Rb to inhibit its PP2A-mediated dephosphorylation upon γ- irradiation. Deregulation of Pin1 can lead to disruptive S-phase checkpoint control. Present commentary aims to briefly discuss the significance of Pin1-Rb signaling in cell cycle control and S-phase checkpoint control.
Pin1 is an unique peptidyl-prolyl cis/trans isomerase conserved from archaea to mammal. Pin1 binds to phosphorylated Ser/Thr-Pro motifs to isomerize peptidyl-proline bonds from cis to trans or vice versa . Phosphorylation is the prerequisite for Pin1 binding to its substrates. Thus, Pin1-catalyzed conformation switch represents a pivotal phosphorylation-dependent mechanism in regulation of cellular signaling [2,3].
By twisting the conformation of target proteins, Pin1 can modulate their stability, activity, cellular localization, phosphorylation status and/or protein-protein interactions. Up till now, more than 60 proteins have been identified as Pin1 substrates, which function in a wide spectrum of cellular events including cell cycle progression, proliferation, survival, differentiation, tumorigenesis and morphogenesis [4,5]. Pin1 coordinates cell division in cycling cells by targeting Cyclin D1, ErbB2/Ras, Wnt/β-catenin, and NF-κB signaling pathways [6-9].
Specifically, Pin1 contributes exclusively to tumorogenesis and cancer progress by isomerizing a series of proline-directed kinases, such as glycogen synthase kinase 3 beta, cyclin-dependent kinases and MAP kinases [4,5,10]. Pin1 has been also shown to participate in cellular response to genotoxic stress through interaction and activation of phosphorylatd p53 [11,12]. In addition, several reports revealed an important function of Pin1 in the modulation of self-renewal, pluripotency and differentiation of stem cells through pluripotent factors such as Nanog and Oct4 [13,14].
Retinoblastoma protein (Rb), the first identified tumor suppressor protein, is an essential regulator of cell cycle progression, apoptosis, senescence and differentiation. Regulation of Rb phosphorylation is the major mechanism for the modulation of Rb activity. Hypophosphorylated Rb interacts with E2F, a transcription factor involved in cell cycle progression and survival. Conversely, hyperphosphorylated Rb is unable to bind E2F proteins, thereby allowing E2F to promote cell cycle progression. Cyclin/Cyclin-dependent kinase (CDK) complexes are primarily responsible for phosphorylation of Rb, while protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) are responsible for dephosphorylation of Rb .
We have previously demonstrated that Pin1 deficiency leads to a decrease in Cyclin D1 expression, resulting in reduced Rb phosphorylation. IGF-1 can induce Pin1 protein expression which promotes cyclin D1-dependent Rb phosphorylation and cell cycle S-phase entry .
In our recent study, we found that Pin1 can directly bind to Rb to modulate its phosphorylation. Pin1 WW domain binds to Rb C-pocket. G1-S Cyclins promote Rb phosphorylation and facilitates Pin1- Rb interaction, leading to inhibition of PP2A-mediated Rb dephosphorylation. Importantly, we found that overexpression of Pin1 leads to hyperphosphorylated Rb and defective S-phase checkpoint control in response to γ-irradiation. Thus, deregulation of Pin1 expression can disrupt S-phase checkpoint control upon DNA damage, which may contribute to genomic instability important for tumorigenesis. Consistent with this notion, we found that Pin1 overexpression is closely associated with Rb hyperphosphorylation in human breast cancer biopsies, suggesting an important pathological role for Pin1-Rb signaling in cancer development .
In summary, our studies demonstrate that Pin1 is a critical regulator of Rb activity (Figure 1). On one hand, Pin1 activates cyclin D1 to facilitate Rb hyperphosphorylation. On the other hand, Pin1 directly binds to Rb and inhibits PP2A-mediated Rb dephosphorylation in response toγ-irradiation. By both ways, hyperphosphorylated Rb loses its function in cell cycle control at G1-S transition and disrupts S-phase check point control.
Pin1-mediated regulation of Rb phosphorylation adds a fine switcher for the modulation of Rb function. This is consistent with a previous report that phosphorylation of Ser608/612 in Rb spacer domain facilitates Pin1-Rb binding and further boosting Rb phosphorylation at S780. Pin1 knockdown leads to G1 arrest and reduced proliferation rate in T98G glioblastoma cells . Abnormally high expression of Pin1 accompanying with increased Rb phosphorylation was discovered in many types of tumors [17,19,20]. In the near future, major challenges will include a better understanding of the molecular regulation of Pin1-Rb signaling in response to physiological and pathological growth stimuli, and more comprehensive studies investigating Pin1-Rb signaling in governing cellular proliferation, apoptosis, senescence and differentiation.
This work was supported by the National Key Basic Research Program (973 Program) of China (2012CB910700).