BACKGROUND & AIMS: :The peptidylprolyl isomerase Pin1 is over-expressed in some human diseases including malignancies and chronic inflammatory diseases, this suggests that it contributes to the constitutive activation of certain intracellular signaling pathways that promote cell proliferation and cell invasion. Here, we investigate the possible role of Pin1 in rheumatoid arthritis (RA). Pin1 expression was immunohistochemically analyzed in synovial tissue (ST) obtained from patients with RA and osteoarthritis (OA). To investigate the correlation between Pin1 and motility and proliferation of synovial cells, Pin1 localization was immunohistochemically compared with matrix metalloproteinase (MMP)-1, MMP-3, and proliferating cell nuclear antigen (PCNA). Double immunofluorescent staining for Pin1 and p65 was performed to determine whether Pin1 is involved in nuclear factor κB (NF-κB) activation in RA-ST. Results showed Pin1 expression was significantly higher in RA-ST than in OA-ST. The expression of MMP-1, MMP-3, and PCNA was also significantly elevated in RA-ST. Double immunofluorescent staining revealed colocalization of Pin1 and p65 in the nuclei of RA-ST. These results suggest that Pin1 may be involved in the pathogenesis of RA binding with p65 to activate the proteins MMP-1, MMP-3, and PCNA. Therefore, Pin1 may play a pivotal role in the pathogenesis of RA.

背景与目标： : 肽酰脯氨酰异构酶Pin1在某些人类疾病 (包括恶性肿瘤和慢性炎症性疾病) 中过表达，这表明它有助于某些细胞内信号通路的组成性激活，从而促进细胞增殖和细胞侵袭。在这里，我们研究Pin1在类风湿关节炎 (RA) 中的可能作用。免疫组织化学分析了从RA和骨关节炎 (OA) 患者获得的滑膜组织 (ST) 中的Pin1表达。为了研究Pin1与滑膜细胞运动和增殖之间的关系，将Pin1定位与基质金属蛋白酶 (MMP)-1，MMP-3和增殖细胞核抗原 (PCNA) 进行了免疫组织化学比较。对Pin1和p65进行双重免疫荧光染色，以确定Pin1是否参与RA-ST中核因子 κ b (NF-κ b) 的激活。结果显示，Pin1在ra-st中的表达显着高于oa-st。在ra-st中，MMP-1，MMP-3和PCNA的表达也显着升高。双重免疫荧光染色显示Pin1和p65在RA-ST核中共定位。这些结果表明，Pin1可能参与RA与p65结合以激活MMP-1，MMP-3和PCNA蛋白的发病机理。因此，Pin1可能在RA的发病机理中起关键作用。

BACKGROUND & AIMS: :Pin1 is an essential mitotic regulator consisting of a peptidyl-prolyl isomerase (PPIase) domain flexibly tethered to a smaller Trp-Trp (WW) binding domain. Communication between these domains is important for Pin1 in vivo activity; however, the atomic basis for this communication has remained elusive. Our previous nuclear magnetic resonance (NMR) studies of Pin1 functional dynamics suggested that weak interdomain contacts within Pin1 enable allosteric communication between the domain interface and the distal active site of the PPIase domain.1,2 A necessary condition for this hypothesis is that the intrinsic properties of the PPIase domain should be sensitive to interdomain contact. Here, we test this sensitivity by generating a Pin1 mutant, I28A, which weakens the wild-type interdomain contact while maintaining the overall folds of the two domains. Using NMR, we show that I28A leads to altered substrate binding affinity and isomerase activity. Moreover, I28A causes long-range perturbations to conformational flexibility in both domains, for both the apo and substrate-complexed states of the protein. These results show that the distribution of conformations sampled by the PPIase domain is sensitive to interdomain contact and strengthen the hypothesis that such contact supports interdomain allosteric communication in Pin1. Other modular systems may exploit interdomain interactions in a similar manner.

背景与目标： : Pin1是一种必需的有丝分裂调节剂，由肽基-脯氨酰异构酶 (PPIase) 结构域组成，灵活地束缚在较小的Trp-Trp (WW) 结合结构域上。这些结构域之间的交流对于Pin1的体内活性很重要; 但是，这种交流的原子基础仍然难以捉摸。我们先前对Pin1功能动力学进行的核磁共振 (NMR) 研究表明，Pin1内的弱域间接触使域界面与PPIase域的远端活性位点之间的变构通讯成为可能。1,2该假设的必要条件是PPIase域的固有特性应对域间接触敏感。在这里，我们通过生成Pin1突变体I28A来测试这种敏感性，该突变体削弱了野生型域间接触，同时保持了两个域的整体褶皱。使用NMR，我们显示I28A导致改变的底物结合亲和力和异构酶活性。此外，对于蛋白质的载脂蛋白和底物络合态，I28A会在两个结构域中引起构象灵活性的远距离扰动。这些结果表明，由PPIase结构域采样的构象分布对结构域间接触敏感，并加强了这种接触支持pin1中结构域间变构通讯的假设。其他模块化系统可以以类似的方式利用域间相互作用。

BACKGROUND & AIMS: :The Myc oncoprotein is considered a master regulator of gene transcription by virtue of its ability to modulate the expression of a large percentage of all genes. However, mechanisms that direct Myc's recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated Myc and its coactivators to select promoters during gene activation, followed by promoting Myc's release associated with its degradation. This facilitates Myc's activation of genes involved in cell growth and metabolism, resulting in enhanced proproliferative activity, even while controlling Myc levels. In cancer cells with impaired Myc degradation, Pin1 still enhances Myc DNA binding, although it no longer facilitates Myc degradation. Thus, we find that Pin1 and Myc are cooverexpressed in cancer, and this drives a gene expression pattern that we show is enriched in poor-outcome breast cancer subtypes. This study provides new insight into mechanisms regulating Myc DNA binding and oncogenic activity, it reveals a novel role for Pin1 in the regulation of transcription factors, and it elucidates a mechanism that can contribute to oncogenic cooperation between Pin1 and Myc.

背景与目标： : Myc癌蛋白因其调节大部分基因表达的能力而被认为是基因转录的主要调节剂。然而，尚未很好地阐明将Myc募集到DNA和靶基因选择以引发特定细胞功能的机制。在这里，我们报告了Pin1脯氨酰异构酶增强丝氨酸62-磷酸化Myc及其共激活剂的募集，以在基因激活过程中选择启动子，然后促进Myc与其降解相关的释放。这有助于Myc激活参与细胞生长和代谢的基因，从而增强增殖活性，即使在控制Myc水平的同时也是如此。在Myc降解受损的癌细胞中，Pin1仍然增强Myc DNA结合，尽管它不再促进Myc降解。因此，我们发现Pin1和Myc在癌症中共表达，这驱动了我们显示的基因表达模式在不良结局的乳腺癌亚型中富集。这项研究为调节Myc DNA结合和致癌活性的机制提供了新的见解，它揭示了Pin1在转录因子调节中的新作用，并阐明了一种可能有助于Pin1和Myc之间致癌合作的机制。

BACKGROUND & AIMS: :PIN1 proteins are a class of peptidyl prolyl cis-trans isomerases (PPIases), which have been implicated in numerous cellular functions like cell cycle progression, transcriptional control, signal transduction, promotion of oncogenesis and host-parasite interactions. In this work, the unfolding mechanism of a single domain PIN1 from Leishmania major (LmPIN1) has been characterized during thermal and denaturant-induced unfolding by differential scanning calorimetry (DSC), fluorescence and circular dichroism. Further, MD simulations have been performed to structurally probe the possible stages of its unfolding process. Both the fluorescence and CD data confirm classical two-state unfolding transitions for urea and GdnHCl. The thermal unfolding of LmPIN1, characterized by DSC, could optimally be fitted to a non two-state transition curve exhibiting two Tm's (53 °C and 57 °C) suggesting the possibility of an intermediate. Thermal unfolding of the modeled LmPIN1 by MD simulation shows that the unfolding process is initiated by increased fluctuations (dynamics) spanning residues 70-80, followed by perturbations in the sheet system and disjuncture of helix-sheet packing. Importantly, simulation and fluorescence quenching studies clearly suggest the possibility of the presence of residual structures of LmPIN1 even after complete denaturation.

背景与目标： : PIN1蛋白是一类肽基脯氨酰顺反式异构酶 (PPIases)，与许多细胞功能有关，例如细胞周期进程，转录控制，信号转导，促进肿瘤发生和宿主-寄生虫相互作用。在这项工作中，通过差示扫描量热法 (DSC)，荧光和圆二色性表征了来自利什曼原虫 (LmPIN1) 的单域PIN1在热和变性剂诱导的展开过程中的展开机理。此外，已经进行了MD模拟，以从结构上探究其展开过程的可能阶段。荧光和CD数据都证实了尿素和GdnHCl的经典双态展开跃迁。以DSC为特征的LmPIN1的热展开可以最佳地拟合为具有两个Tm (53 °C和57 °C) 的非两态转变曲线，表明存在中间体的可能性。通过MD模拟对建模的LmPIN1进行的热展开表明，展开过程是由跨越70-80的残余物的波动 (动力学) 增加引发的，随后是片材系统的扰动和螺旋片材填料的分离。重要的是，模拟和荧光猝灭研究清楚地表明，即使完全变性后，LmPIN1的残留结构也可能存在。

BACKGROUND & AIMS: BACKGROUNDS:Vascular atherosclerosis leads to various cardiovascular and cerebrovascular diseases. Nitric oxide (NO) promotes vasodilatation and prevents Coronary Artery Disease (CAD). Pin1 suppresses NO production by down-regulating the activity of endothelial nitric oxide synthase (eNOS). Whether the genetic polymorphisms of the PIN1 gene (encoding Pin1) are implicated in CAD deserves investigations in human beings. METHODS:A total of 210 CAD patients and control individuals (all females) were enrolled, and their genotypes of rs2233679 (-667C/T, a key SNP in the promoter of PIN1 gene) were sequenced. T-test, chi-square test, odds ratio (OR) and 95% confidence interval (95% CI) were calculated to evaluate Hardy-Weinberg equilibrium, varied genetic distribution and relative CAD risk. RESULTS:The differences in age, BMI, triglyceride, total cholesterol, low-density and high density cholesterol between the CAD and control groups were not significant (all P>0.05), and Hardy-Weinberg equilibrium was observed in the two groups (both P>0.05). The frequency of -667T allele in the CAD group was higher than that in the control group. The genotype -667TT elicited a higher hazardous risk of CAD compared to the genotype -667CC (OR=1.85, 95% CI: 0.75-4.53) as well as the genotypes CC+CT (OR=1.97, 95% CI: 0.86-4.49). CONCLUSIONS:We firstly show that the allele -667T in the PIN1 promoter may elicit a higher CAD-risk than -667C, and the -667TT genotype of PIN1 may be a new genetic biomarker for increased incidence of CAD. These novel observations put forward a new understanding of the PIN1-CAD genetic relationship in humans, potentially contributing to both cardiovascular and cerebrovascular disorders.

背景与目标：

BACKGROUND & AIMS: :The infiltration, accumulation and degranulation of eosinophils in the lung represents a hallmark of active asthma. In vivo or in vitro eosinophil activation triggers the secretion of the antiapoptotic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). We now identify Pin1, a cis-trans isomerase, as an essential component of the ribonucleoprotein complex responsible for GM-CSF mRNA stabilization, cytokine secretion and the survival of activated eosinophils. Pin1 regulated the association of the AU-rich element-binding proteins AUF1 and hnRNP C with GM-CSF mRNA, accelerating or slowing decay, respectively. These data indicate Pin1 is a key mediator of GM-CSF production.

背景与目标： : 嗜酸性粒细胞在肺中的浸润，积累和脱颗粒代表了活动性哮喘的标志。体内或体外嗜酸性粒细胞激活触发抗凋亡细胞因子粒细胞-巨噬细胞集落刺激因子 (gm-csf) 的分泌。现在，我们将顺式-反式异构酶Pin1鉴定为核糖核蛋白复合物的重要组成部分，负责gm-csf mRNA的稳定，细胞因子的分泌和活化的嗜酸性粒细胞的存活。Pin1调节富含AU的元素结合蛋白AUF1和hnRNP C与gm-csf mRNA的关联，分别加速或减缓衰变。这些数据表明Pin1是gm-csf产生的关键介质。

BACKGROUND & AIMS: :The reticulate leaf vein pattern typical of angiosperms is proposed to have been a driving force for their evolutionary success. Vein pattern is established through auxin canalization via the auxin efflux protein PINFORMED1 (PIN1). During formation of vein loops, PIN1 cellular localization is increasingly restricted to either the basal side of cells in the lower domain or to the apical side in the upper domain. We previously identified the gene FORKED1 (FKD1) to be required for PIN1 asymmetric localization and for the formation of closed vein loops. FKD1 encodes a plant-specific protein with a domain of unknown function (DUF828) and a Pleckstrin-like homology domain. The Arabidopsis genome encodes eight similar proteins, which we term the FORKED1-LIKE (FL) gene family. Five FL family members localize primarily to the trans-Golgi network or the Golgi, and several co-localize with FKD1-green flourescent protein (GFP) and RABA1c, suggesting action in the secretory pathway. While single FL gene family mutations do not result in vein pattern defects, triple mutants with mutations in FKD1, FL2, and FL3 result in a more symmetric PIN1 localization and a highly disconnected vein pattern. Our data suggest that FL genes act redundantly with FKD1 in the secretory pathway to establish appropriate PIN1 localization in provascular tissue.

背景与目标： : 被子植物典型的网状叶脉模式被认为是其进化成功的驱动力。通过生长素外排蛋白PINFORMED1 (PIN1) 通过生长素管化建立静脉模式。在形成静脉环的过程中，PIN1细胞的定位越来越局限于下部结构域的细胞的基底侧或上部结构域的顶端侧。我们先前确定了PIN1不对称定位和形成闭合静脉环所必需的基因forkd1 (FKD1)。FKD1编码具有未知功能结构域 (DUF828) 和类似Pleckstrin的同源结构域的植物特异性蛋白。拟南芥基因组编码八种相似的蛋白质，我们称之为FORKED1-LIKE (FL) 基因家族。五个FL家族成员主要定位于跨高尔基体网络或高尔基体，几个与FKD1-green荧光蛋白 (GFP) 和RABA1c共同定位，表明在分泌途径中起作用。虽然单个FL基因家族突变不会导致静脉模式缺陷，但FKD1，FL2和FL3突变的三重突变体会导致更对称的PIN1定位和高度断开的静脉模式。我们的数据表明，FL基因在分泌途径中与FKD1重复作用，以在血管组织中建立适当的PIN1定位。

BACKGROUND & AIMS: :The response of eosinophils (Eos) to respiratory virus has emerged as an important link between pulmonary infection and allergic asthmatic exacerbations. Eos activate innate immune responses through TLR signaling. In this study, using mouse and human Eos and mice lacking the prolyl isomerase Pin1 selectively in Eos, we show that Pin1 is indispensable for eosinophilopoiesis in the bone marrow (BM) and mature cell function in the presence of TLR7 activation. Unbiased in vivo analysis of mouse models of allergic airway inflammation revealed that TLR7 activation in knockout mice resulted in systemic loss of Eos, reduced IFN production, and an inability to clear respiratory viruses. Consistent with this finding, BM mouse Eos progenitors lacking Pin1 showed markedly reduced cell proliferation and survival after TLR7 activation. Mechanistically, unlike wild-type cells, Pin1 null mouse Eos were defective in the activation of the endoplasmic reticulum stress-induced unfolded protein response. We observed significant reductions in the expression of unfolded protein response components and target genes, aberrant TLR7 cleavage and trafficking, and reduced granule protein production in knockout Eos. Our data strongly suggest that Pin1 is required for BM Eos generation and function during concurrent allergen challenge and viral infection.

背景与目标： : 嗜酸性粒细胞 (Eos) 对呼吸道病毒的反应已成为肺部感染与过敏性哮喘发作之间的重要联系。Eos通过TLR信号激活先天免疫反应。在这项研究中，使用小鼠和人Eos以及在Eos中选择性地缺乏脯氨酰异构酶Pin1的小鼠，我们表明Pin1对于存在TLR7激活的骨髓 (BM) 中的嗜酸性粒细胞生成和成熟细胞功能是必不可少的。对过敏性气道炎症小鼠模型的无偏体内分析表明，敲除小鼠中的TLR7激活导致Eos的全身性损失，IFN产生减少以及无法清除呼吸道病毒。与这一发现一致，缺乏Pin1的BM小鼠Eos祖细胞在TLR7激活后显示出明显降低的细胞增殖和存活。从机制上讲，与野生型细胞不同，Pin1无效小鼠Eos在内质网应激诱导的未折叠蛋白反应的激活方面存在缺陷。我们观察到基因敲除Eos中未折叠蛋白反应成分和靶基因的表达显着降低，TLR7的异常裂解和运输以及颗粒蛋白的产生减少。我们的数据强烈表明，在同时发生过敏原激发和病毒感染期间，BM Eos的产生和功能需要Pin1。

BACKGROUND & AIMS: :Protein tyrosine phosphatase (PTP)-PEST is a critical regulator of cell adhesion and migration. However, the mechanism by which PTP-PEST is regulated in response to oncogenic signaling to dephosphorylate its substrates remains unclear. Here, we demonstrate that activated Ras induces extracellular signal-regulated kinase 1 and 2-dependent phosphorylation of PTP-PEST at S571, which recruits PIN1 to bind to PTP-PEST. Isomerization of the phosphorylated PTP-PEST by PIN1 increases the interaction between PTP-PEST and FAK, which leads to the dephosphorylation of FAK Y397 and the promotion of migration, invasion, and metastasis of v-H-Ras-transformed cells. These findings uncover an important mechanism for the regulation of PTP-PEST in activated Ras-induced tumor progression.

背景与目标： 蛋白质酪氨酸磷酸酶 (PTP)-PEST是细胞粘附和迁移的关键调节剂。然而，PTP-PEST响应致癌信号调节其底物去磷酸化的机制仍不清楚。在这里，我们证明了活化的Ras在S571处诱导细胞外信号调节的PTP-PEST激酶1和2依赖性磷酸化，从而募集PIN1与PTP-PEST结合。PIN1对磷酸化的PTP-PEST的异构化增加了PTP-PEST与FAK之间的相互作用，从而导致FAK Y397的去磷酸化以及促进v-H-Ras转化细胞的迁移，侵袭和转移。这些发现揭示了在激活的Ras诱导的肿瘤进展中调节PTP-PEST的重要机制。

BACKGROUND & AIMS: :The peptidyl-prolyl cis-trans isomerase (PPIase) Pin1 modulates the activity of a range of target proteins involved in the cell cycle, transcription, translation, endocytosis, and apoptosis by facilitating dephosphorylation of phosphorylated serine or threonine residue preceding a proline (p-Ser/Thr-Pro) motifs catalyzed by phosphatases specific for the trans conformations. Pin1 targets include the neuronal microtubule-associated protein tau, whose dephosphorylation restores its ability to stabilize microtubules. We, and others, have shown that tau hyperphosphorylation in the neurofibrillary tangles (NFTs) of Alzheimer disease (AD) is associated with redirection of the predominantly nuclear Pin1 to the cytoplasm and with Pin1 shortfalls throughout subcellular compartments. As nuclear Pin1 depletion causes apoptosis, shortfalls in regard to both nuclear and p-tau targets may contribute to neuronal dysfunction. We report here that similar Pin1 redistribution and shortfalls occur in frontotemporal dementias (FTDs) characterized by abnormal protein aggregates of tau and other cytoskeletal proteins. This may be a unifying, contributory factor towards neuronal death in these dementias.

背景与目标： : 肽基-脯氨酰顺式反式异构酶 (PPIase) Pin1调节一系列参与细胞周期，转录，翻译，内吞作用的靶蛋白的活性，通过促进对反式构象特异的磷酸酶催化的脯氨酸 (p-Ser/Thr-Pro) 基序之前的磷酸化丝氨酸或苏氨酸残基的去磷酸化而凋亡。Pin1靶标包括神经元微管相关蛋白tau，其去磷酸化恢复其稳定微管的能力。我们和其他人已经表明，阿尔茨海默氏病 (AD) 的神经原纤维缠结 (nft) 中的tau过度磷酸化与主要的核Pin1重定向到细胞质以及整个亚细胞区室的Pin1不足有关。由于核Pin1耗竭会导致细胞凋亡，因此核和p-tau靶标的不足可能会导致神经元功能障碍。我们在此报告说，以tau蛋白和其他细胞骨架蛋白的异常蛋白聚集体为特征的额颞叶痴呆 (FTDs) 中也发生了类似的Pin1再分配和不足。这可能是导致这些痴呆症神经元死亡的统一因素。

BACKGROUND & AIMS: :Pin1 protein, a peptidyl-prolyl cis-trans isomerase plays an important regulatory role in neuronal function. Recent studies indicate that Pin1 may promote the dephosphorylation of tau and restore its ability to bind to and polymerize microtubles. Previous studies on postmortem human brains showed that Pin1 is down-regulated in advanced Alzheimer's disease (AD) brains compared to age-matched non-demented controls. Because AD is a slowly progressive disease with a preclinical period that can last years, the abundance and regulatory function of Pin1 may vary on the course of the disease. In order to evaluate the potential contribution of Pin1 to AD pathogenesis, levels of mRNA, protein and isomerase activity of Pin1 and phosphorylated tau from postmortem brains of 10 persons with mild-cognitive impairment (MCI), 10 with AD and 10 age-matched no cognitive impairment (NCI) were measured. The relationship between Pin1 and phosphorylated tau as well as clinical and cognitive data were analyzed. The results indicated that Pin1 activity in MCI and AD were significantly higher than in NCI. Phosphorylated tau in MCI and AD was also higher than in NCI group. The positive correlation trend in MCI and the robust correlation in AD between Pin1 activity and phosphorylated tau implies that increasing phosphorylated tau during AD pathogenesis may induce the compensatory activation/up-regulation of Pin1, while the inverse correlation between Pin1 activity and phosphorylated tau in NCI group implies that decreased Pin1 may play a role in the initial accumulation of phosphorylated tau in AD pathogenesis.

背景与目标： : Pin1蛋白，一种肽基脯氨酰顺反式异构酶，在神经元功能中起重要的调节作用。最近的研究表明，Pin1可能促进tau的去磷酸化并恢复其与微管结合和聚合的能力。先前对死后人脑的研究表明，与年龄匹配的非痴呆对照组相比，晚期阿尔茨海默氏病 (AD) 脑中的Pin1下调。由于AD是一种缓慢进行的疾病，其临床前期可以持续数年，因此Pin1的丰度和调节功能可能会随疾病的发展而变化。为了评估Pin1对AD发病的潜在贡献，测量了10例轻度认知障碍 (MCI)，10例AD和10例年龄匹配的未认知障碍 (NCI) 的死后大脑中Pin1和磷酸化tau的mRNA，蛋白质和异构酶活性。分析了Pin1与磷酸化tau之间的关系以及临床和认知数据。结果表明，MCI和AD的Pin1活性明显高于NCI。MCI和AD的磷酸化tau也高于NCI组。MCI的正相关趋势和AD中Pin1活性与磷酸化tau之间的强相关性表明，在AD发病过程中磷酸化tau的增加可能会诱导Pin1的代偿性激活/上调。而NCI组Pin1活性与磷酸化tau之间的负相关意味着Pin1降低可能在AD发病机理中磷酸化tau的初始积累中起作用。

BACKGROUND & AIMS: :The Hippo signaling pathway controls cellular processes including growth, homeostasis, and apoptosis. The kinase STK3 acts upstream in this pathway to activate LATS1/2 kinase, which phosphorylates and inactivates the transcriptional coactivators YAP/TAZ. The dysregulation of Hippo signaling leads to human diseases including cancer; however, the molecular mechanisms underlying its dysregulation in melanoma are unknown. We aimed to determine the role of the PIN1 in Hippo signaling dysregulation and melanoma tumorigenesis. We report that PIN1 interacts with STK3 and induces ubiquitination-dependent proteasomal degradation of STK3. Furthermore, PIN1 plays a critical role in the nuclear translocation of TAZ, which forms a complex with TEAD to increase CTGF expression. PIN1 ablation blocks TAZ/TEAD complex formation and decreases CTGF expression. PIN1-mediated STK3 degradation is associated with enhanced cell growth, induction of cell transformation, and increased tumorigenicity. In clinical context, PIN1 and STK3 levels are inversely correlated in patient melanoma tissues. These findings indicate that PIN1-mediated STK3 destabilization contributes to the dysregulation of Hippo signaling, leading to oncogenic signaling and melanoma tumorigenesis. Our data suggest that inhibition of the PIN1-STK3 axis could be a novel treatment strategy for malignant melanoma.

背景与目标： : Hippo信号通路控制细胞过程，包括生长，稳态和凋亡。激酶STK3在该途径的上游起作用，以激活LATS1/2激酶，该激酶磷酸化并使转录共激活因子YAP/TAZ失活。河马信号的失调导致人类疾病，包括癌症; 然而，其在黑色素瘤中失调的分子机制尚不清楚。我们旨在确定PIN1在河马信号传导失调和黑色素瘤肿瘤发生中的作用。我们报告PIN1与STK3相互作用并诱导STK3的泛素化依赖性蛋白酶体降解。此外，PIN1在TAZ的核易位中起关键作用，TAZ与TEAD形成复合物以增加CTGF表达。PIN1消融阻断TAZ/TEAD复合物的形成并降低CTGF表达。PIN1-mediated STK3降解与增强的细胞生长，诱导细胞转化和增加的致瘤性有关。在临床情况下，患者黑色素瘤组织中的PIN1和STK3水平呈负相关。这些发现表明，PIN1-mediated STK3不稳定导致Hippo信号传导失调，导致致癌信号传导和黑色素瘤肿瘤发生。我们的数据表明，抑制PIN1-STK3轴可能是恶性黑色素瘤的一种新的治疗策略。

BACKGROUND & AIMS: -2

背景与目标： -2

BACKGROUND & AIMS: :Biodiversity in plant shape is mainly attributable to the diversity of leaf shape, which is largely determined by the transient morphogenetic activity of the leaf margin that creates leaf serrations. However, the precise mechanism underlying the establishment of this morphogenetic capacity remains poorly understood. We report here that INDOLE-3-BUTYRIC ACID RESPONSE 5 (IBR5), a dual-specificity phosphatase, is a key component of leaf-serration regulatory machinery. Loss-of-function mutants of IBR5 exhibited pronounced serrations due to increased cell area. IBR5 was localized in the nucleus of leaf epidermis and petiole cells. Introducing a C129S mutation within the highly conserved VxVHCx2GxSRSx5AYLM motif of IBR5 rendered it unable to rescue the leaf-serration defects of the ibr5-3 mutant. In addition, auxin reporters revealed that the distribution of auxin maxima was expanded ectopically in ibr5-3. Furthermore, we found that the distribution of PIN1 on the plasma membrane of the epidermal and cells around the leaf vein was compromised in ibr5-3. We concluded that IBR5 is essential for the establishment of PIN-FORMED 1 (PIN1)-directed auxin maxima at the tips of leaf serration, which is vital for the elaborated regulation during its formation.

背景与目标： : 植物形状的生物多样性主要归因于叶片形状的多样性，这在很大程度上取决于产生叶片锯齿的叶缘的瞬时形态发生活动。然而，建立这种形态发生能力的确切机制仍然知之甚少。我们在此报告说，吲哚-3-丁酸反应5 (IBR5) 是一种双特异性磷酸酶，是叶片锯齿调节机制的关键组成部分。由于细胞面积增加，IBR5的功能丧失突变体表现出明显的锯齿。IBR5位于叶表皮和叶柄细胞的核中。在IBR5的高度保守的VxVHCx2GxSRSx5AYLM基序中引入C129S突变，使其无法挽救ibr5-3突变体的叶片锯齿缺陷。此外，生长素记者透露，生长素最大值的分布在ibr5-3中是异位扩张的。此外，我们发现PIN1在表皮质膜和叶脉周围细胞上的ibr5-3分布受到损害。我们得出的结论是，IBR5对于在叶片锯齿的尖端建立销钉形成的1 (PIN1) 导向的生长素最大值至关重要，这对于在其形成过程中进行详细的调节至关重要。

BACKGROUND & AIMS: :Interactions involving phosphorylated Ser/Thr-Pro motifs in proteins play a key role in numerous regulatory processes in the cell. Here, we investigate potential ligands of the WW binding domain of Pin1 in order to inhibit protein-protein interactions between Pin1 and phosphopeptides. Our structure-based strategy implies the synthesis of analogues of the Ac-Thr(PO(3)H(2))-Pro-NH(2) dipeptide and relies on high resolution NMR spectroscopy to accurately measure the affinity constants even in the high micromolar range.

背景与目标： : 蛋白质中涉及磷酸化Ser/Thr-Pro基序的相互作用在细胞中的许多调节过程中起关键作用。在这里，我们研究了Pin1的WW结合结构域的潜在配体，以抑制Pin1和磷酸肽之间的蛋白质-蛋白质相互作用。我们基于结构的策略意味着ac-thr (PO(3)H(2))-Pro-NH(2) 二肽的类似物的合成，并且依靠高分辨率NMR光谱来精确测量亲和常数，即使在高微摩尔范围内。