Pin1 Catalyzes Conformational Changes of Thr-187 in p27Kip1 and Mediates Its Stability through a Polyubiquitination Process

Zhou, Wei; Yang, Qiaoyun; Low, Choon Bing; Karthik, Balakrishna Chandrababu; Wang, Yu; Ryo, Akihide; Yao, Shao Q.; Yang, Daiwen; Liou, Yih‐Cherng

doi:10.1074/jbc.m109.022814

Cited by 44 publications

(42 citation statements)

References 61 publications

(47 reference statements)

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“…dyl-prolyl isomerase, recognizes and stabilizes p27 KIP1 when phosphorylated on Thr187 by inducing its conformational change (Zhou et al, 2009). Misregulation that results in increased degradation of p27 KIP1 can be related to cancer development (Hershko, 2008;Mishra et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The function of p27^KIP1during tumor development

2009

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Abbreviations: CDKs, cycle dependent kinases; CKIs, cyclin dependent kinase inhibitors; CRM1, chromosome region maintenance 1 protein; Pin1, peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; RSK1, ribosomal S6 kinase 1; SCF, skp1-cullin1-F-box protein; Skp2, S-phase kinase-associated protein 2 AbstractTimely cell cycle regulation is conducted by sequential activation of a family of serine-threonine kinases called cycle dependent kinases (CDKs). Tight CDK regulation involves cyclin dependent kinase inhibitors (CKIs) which ensure the correct timing of CDK activation in different phases of the cell cycle. One CKI of importance is p27 KIP1. The regulation and cellular localization of p27 KIP1 can result in biologically contradicting roles when found in the nucleus or cytoplasm of both normal and tumor cells. The p27 KIP1 protein is mainly regulated by proteasomal degradation and its downregulation is often correlated with poor prognosis in several types of human cancers. The protein can also be functionally inactivated by cytoplasmic localization or by phosphorylation. The p27 KIP1 protein is an unconventional tumor suppressor because mutation of its gene is extremely rare in tumors, implying the normal function of the protein is deranged during tumor development. While the tumor suppressor function is mediated by p27 KIP1 's inhibitory interactions with the cyclin/CDK complexes, its oncogenic function is cyclin/CDK independent, and in many cases correlates with cytoplasmic localization. Here we review the basic features and novel aspects of the p27 KIP1 protein, which displays genetically separable tumor suppressing and oncogenic functions.

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Section: Introductionmentioning

confidence: 99%

The function of p27^KIP1during tumor development

2009

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“…More recently, it has been demonstrated that Pin1 directly controls the stability of the CDK inhibitor p27 and indirectly controls that of p21. 14 To exclude any functional involvement of the CDK/cyclin complexes in the phenotype observed in PIN1 KD cells, kinase assay experiments were carried out. CDK2, CDK4, and CDK6 (Figure 1e).…”

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confidence: 99%

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

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Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo-to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses. The retinoblastoma protein (pRb), the product of the RB1 gene (i.e., the tumor-suppressor gene involved in hereditary and sporadic retinoblastoma pathogenesis), is mainly responsible for the control of cell proliferation via two different mechanisms. The first is based on the interaction between pRb and different chromatin-modifying enzymes: pRb interacts with histone deacetylases (HDACs) 1, 2, and 3, histone methylase SUV39H1, and chromatin-remodeling enzymes Brg1 and Brm, thus repressing gene expression. 1 The second mechanism involves pRb controlling the cell cycle through interaction with the E2F family of transcription factors 2 in a phosphorylation-dependent way: in early and mid G1, the protein complex D-type cyclins/CDK4, 6 whereas in late G1, cyclins E(A)/CDK2 gradually phosphorylate pRb. Hyperphosphorylated pRb releases E2F transcription factors and allows the expression of genes that mediate entry into the S phase. 3 As pRb protein holds a central role in the cell cycle, its inactivation is necessary for enabling cancer cell proliferation. Different mechanisms of pRb inactivation have been described, although inactivation through phosphorylation is most common in human sporadic cancers. In this context, cyclin D1 overexpression induces CDK4/6 activation and thus pRb hyperphosphorylation. 4,5 In addition, the cyclindependent kinase (CDK) inhibitory partner, p16 protein (i.e.,

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“…Interestingly, both PD98059 and JNK inhibitor treatment abolished Pin1-induced TR3 expression, implying that ERK and JNK may cooperate in phosphorylating TR3 at Ser95 site. Since some ubiquitin E3 ligases or co-factors have a structural preference and specifically bind to phospho-Ser/Thr-Pro motifs in a trans conformation (Orlicky et al, 2003;Siepe and Jentsch, 2009;Zhou et al, 2009), we therefore speculate that Pin1 may convert the phospho-Ser95-Pro motif from a trans isomer to a cis conformation, which is unfavorable for the interaction of E3 ligase to TR3, resulting in stabilizing the TR3 protein. Therefore, identification of E3 ligase for TR3 will be important for further revealing the molecular mechanism of TR3 degradation.…”

Section: Pin1 Regulates Mitogenic Function Of Tr3mentioning

confidence: 99%

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

Wang

et al. 2011

Oncogene

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Pin1 regulates a subset of phosphoproteins by isomerizing phospho-Ser/Thr-Pro motifs via a 'post-phosphorylation' mechanism. Here, we characterize TR3 as a novel Pin1 substrate, and the mitogenic function of TR3 depends on Pin1-induced isomerization. There are at least three phospho-Ser-Pro motifs on TR3 that bind to Pin1. The Ser95-Pro motif of TR3 is the key site through which Pin1 enhances TR3 stability by retarding its degradation. Pin1 can also catalyze TR3 through phospho-Ser431-Pro motif, which is phosphorylated by extracellular signalregulated kinase 2 (ERK2), resulting in enhanced TR3 transactivation. Furthermore, Pin1 not only facilitates TR3 targeting to the promoter of cyclin D2, a novel downstream target of TR3, but also promotes TR3 to recruit p300, thereby inducing cell proliferation. Importantly, we found that Pin1 is indispensable for TR3 to promote tumor growth both in vitro and in vivo. Our study thus suggests that Pin1 has an important role in cell proliferation by isomerizing TR3.

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Pin1 Catalyzes Conformational Changes of Thr-187 in p27Kip1 and Mediates Its Stability through a Polyubiquitination Process

Cited by 44 publications

References 61 publications

The function of p27^KIP1during tumor development

The function of p27^KIP1during tumor development

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

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Pin1 Catalyzes Conformational Changes of Thr-187 in p27Kip1 and Mediates Its Stability through a Polyubiquitination Process

Cited by 44 publications

References 61 publications

The function of p27KIP1during tumor development

The function of p27KIP1during tumor development

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

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The function of p27^KIP1during tumor development

The function of p27^KIP1during tumor development