The activation of the activating protein-1 (AP-1) family of transcription factors, including c-Fos and c-Jun family members, is one of the earliest nuclear events induced by growth factors that stimulate extracellular signal-regulated kinases (ERKs). In the case of c-Fos, the activation of ERK leads to an increased expression of c-fos mRNA. In turn, we have recently shown that ERK phosphorylates multiple residues within the carboxylterminal transactivation domain (TAD) of c-Fos, thus resulting in its increased transcriptional activity. However, how ERK-dependent phosphorylation regulates c-Fos function is still poorly understood. In this regard, it has been recently observed that the prolyl isomerase Pin1 can interact with proteins phosphorylated on serine or threonine residues that precede prolines (pS/T-P), such as the transcription factors p53 and c-Jun, thereby controlling their activity by promoting the cis-trans isomerization of these pS/T-P bonds. Here, we found that Pin1 binds c-Fos through specific pS/T-P sites within the c-Fos TAD, and that this interaction results in an enhanced transcriptional response of c-Fos to polypeptide growth factors that stimulate ERK. Our findings suggest that c-Fos represents a novel target for the isomerizing activity of Pin1 and support a role for Pin1 in the mechanism by which c-Jun and c-Fos can cooperate to regulate AP-1-dependent gene transcription upon phosphorylation by mitogen-activated kinase (MAPK) family members.

Long timescale (>1 micros) molecular dynamics simulations of protein folding offer a powerful tool for understanding the atomic-scale interactions that determine a protein's folding pathway and stabilize its native state. Unfortunately, when the simulated protein fails to fold, it is often unclear whether the failure is due to a deficiency in the underlying force fields or simply a lack of sufficient simulation time. We examine one such case, the human Pin1 WW domain, using the recently developed deactivated morphing method to calculate free energy differences between misfolded and folded states. We find that the force field we used favors the misfolded states, explaining the failure of the folding simulations. Possible further applications of deactivated morphing and implications for force field development are discussed.

Host proteins are incorporated both on and inside human immunodeficiency virus type 1 (HIV-1) virions. To identify cellular proteins inside HIV-1, virion preparations were treated by a protease-digestion technique that removes external host proteins, allowing for the study of the proteins inside the virus. Treated HIV-1 preparations were analyzed by immunoblot, high-pressure liquid chromatography, and protein sequence analyses. These analyses identified several cellular proteins inside HIV-1: elongation factor 1alpha, glyceraldehyde-3-phosphate dehydrogenase, HS-1, phosphatidylethanolamine-binding protein, Pin1, Lck, Nm23-H1, and the C-terminal tail of CD43. Several of these proteins were found as fragments of their full-sized proteins that appear to be generated by our protease treatment of the virions, the HIV-1 protease, or a cellular protease. Recent advances in cell biology and biochemistry have identified some of these proteins as actin-binding proteins. These results support the hypothesis that actin filaments are incorporated into the virion and may provide additional clues for the understanding of the interaction between viral and cellular proteins during assembly and budding.

Sphingolipids are a class of structural membrane lipids involved in membrane trafficking and cell polarity. Functional analysis of the ceramide synthase family in Arabidopsis thaliana demonstrates the existence of two activities selective for the length of the acyl chains. Very-long-acyl-chain (C>> 18 carbons) but not long-chain sphingolipids are essential for plant development. Reduction of very-long-chain fatty acid sphingolipid levels leads in particular to auxin-dependent inhibition of lateral root emergence that is associated with selective aggregation of the plasma membrane auxin carriers AUX1 and PIN1 in the cytosol. Defective targeting of polar auxin carriers is characterized by specific aggregation of Rab-A2(a)- and Rab-A1(e)-labeled early endosomes along the secretory pathway. These aggregates correlate with the accumulation of membrane structures and vesicle fragmentation in the cytosol. In conclusion, sphingolipids with very long acyl chains define a trafficking pathway with specific endomembrane compartments and polar auxin transport protein cargoes.

The Ess1/Pin1 peptidyl-prolyl isomerase (PPIase) is thought to control mitosis by binding to cell cycle regulatory proteins and altering their activity. Here we isolate temperature-sensitive ess1 mutants and identify six multicopy suppressors that rescue their mitotic-lethal phenotype. None are cell cycle regulators. Instead, five encode proteins involved in transcription that bind DNA, modify chromatin structure or are regulatory subunits of RNA polymerase II. A sixth suppressor, cyclophilin A, is a member of a distinct family of PPIases that are targets of immuno suppressive drugs. We show that the expression of some but not all genes is decreased in ess1 mutants, and that Ess1 interacts with the C-terminal domain (CTD) of RNA polymerase II in vitro and in vivo. The results forge a strong link between PPIases and the transcription machinery and suggest a new model for how Ess1/Pin1 controls mitosis. In this model, Ess1 binds and isomerizes the CTD of RNA polymerase II, thus altering its interaction with proteins required for transcription of essential cell cycle genes.

Virus infection induces host antiviral responses including induction of type I IFNs. Transcription factor IFN regulatory factor 3 (IRF3) plays an essential role and is tightly regulated in this process. Herein we report that TRIM21 (tripartite motif-containing 21) is significantly induced and interacts with IRF3 upon RNA virus infection. Ectopic expression or knockdown of TRIM21 could respectively enhance or impair IRF3-mediated gene expression. Mechanistically, TRIM21 interferes with the interaction between Pin1 (peptidyl-prolyl cis/trans isomerase, NIMA-interacting 1) and IRF3, thus preventing IRF3 ubiquitination and degradation. A conserved motif in the B 30.2 domain of TRIM21 is critical for its modulation of IRF3 function, while the RING finger is dispensable. Host antiviral responses are significantly boosted or crippled in the presence or absence of TRIM21. Our results identify TRIM21 as an essential modulator of IRF3 stability and demonstrate that it positively regulates the strength and duration of primary antiviral response, thus further strengthening the notion that the TRIM family is evolutionarily integrated with innate immunity.

Tumor hypoxia is associated with disease progression and treatment failure, but the hypoxia signaling mechanism is not fully understood. Here, we show that KLHL20, a Cullin3 (Cul3) substrate adaptor induced by HIF-1, coordinates with the actions of CDK1/2 and Pin1 to mediate hypoxia-induced PML proteasomal degradation. Furthermore, this PML destruction pathway participates in a feedback mechanism to maximize HIF-1α induction, thereby potentiating multiple tumor hypoxia responses, including metabolic reprogramming, epithelial-mesenchymal transition, migration, tumor growth, angiogenesis, and chemoresistance. In human prostate cancer, overexpression of HIF-1α, KLHL20, and Pin1 correlates with PML down-regulation, and hyperactivation of the PML destruction pathway is associated with disease progression. Our study indicates that the KLHL20-mediated PML degradation and HIF-1α autoregulation play key roles in tumor progression.

Pin1 is an essential protein that can peptidyl-prolyl-isomerize small phosphopeptides. It has been suggested that Pin1 regulates entry into mitosis by catalyzing the cis/trans-isomerization of prolines on critical protein substrates in response to phosphorylation. We show that Pin1 catalytically generates a conformational change on the mitotic phosphatase Cdc25, as assayed by limited protease digestion, differential reactivity to a phosphoserine-proline-directed monoclonal antibody (MPM-2), and by changes in Cdc25 enzymatic activity. Pin1 catalytically modifies the conformation of Cdc25 at stoichiometries less than 0.0005, and mutants of Pin1 in the prolyl isomerase domain are not active. We suggest that, although difficult to detect, phosphorylation-dependent conformational changes mediated by prolyl isomerization may play an important regulatory role in the cell cycle.

Somatic embryogenesis requires auxin and establishment of the shoot apical meristem (SAM). WUSCHEL (WUS) is critical for stem cell fate determination in the SAM of higher plants. However, regulation of WUS expression by auxin during somatic embryogenesis is poorly understood. Here, we show that expression of several regulatory genes important in zygotic embryogenesis were up-regulated during somatic embryogenesis of Arabidopsis. Interestingly, WUS expression was induced within the embryonic callus at a time when somatic embryos could not be identified morphologically or molecularly. Correct WUS expression, regulated by a defined critical level of exogenous auxin, is essential for somatic embryo induction. Furthermore, it was found that auxin gradients were established in specific regions that could then give rise to somatic embryos. The establishment of auxin gradients was correlated with the induced WUS expression. Moreover, the auxin gradients appear to activate PIN1 polar localization within the embryonic callus. Polarized PIN1 is probably responsible for the observed polar auxin transport and auxin accumulation in the SAM and somatic embryo. Suppression of WUS and PIN1 indicated that both genes are necessary for embryo induction through their regulation of downstream gene expression. Our results reveal that establishment of auxin gradients and PIN1-mediated polar auxin transport are essential for WUS induction and somatic embryogenesis. This study sheds new light on how auxin regulates stem cell formation during somatic embryogenesis.

The tumor-suppressor function of p53 relies on its transcriptional activity, which is modulated by post-translational modifications and interactions with regulatory proteins. The prolyl isomerase Pin1 has a central role in transducing phosphorylation of p53 into conformational changes that affect p53 stability and function. We found that Pin1 is required for efficient loading of p53 on target promoters upon stress. In addition, Pin1 is recruited to chromatin by p53 and stimulates binding of the p300 acetyltransferase and consequent p53 acetylation. Accordingly, tumor-associated mutations at Pin1-binding residues within the p53 proline-rich domain hamper acetylation of p53 by p300. After phosphorylation of p53 at Ser46 triggered by cytotoxic stimuli, Pin1 also mediates p53's dissociation from the apoptosis inhibitor iASPP, promoting cell death. In tumors bearing wild-type p53, expression of Pin1 and iASPP are inversely correlated, supporting the clinical relevance of these interactions.

A phospho-carboxyl-terminal domain (CTD) affinity column created with yeast CTD kinase I and the CTD of RNA polymerase II was used to identify Ess1/Pin1 as a phospho-CTD-binding protein. Ess1/Pin1 is a peptidyl prolyl isomerase involved in both mitotic regulation and pre-mRNA 3'-end formation. Like native Ess1, a GSTEss1 fusion protein associates specifically with the phosphorylated but not with the unphosphorylated CTD. Further, hyperphosphorylated RNA polymerase II appears to be the dominant Ess1 binding protein in total yeast extracts. We demonstrate that phospho-CTD binding is mediated by the small WW domain of Ess1 rather than the isomerase domain. These findings suggest a mechanism in which the WW domain binds the phosphorylated CTD of elongating RNA polymerase II and the isomerase domain reconfigures the CTD though isomerization of proline residues perhaps by a processive mechanism. This process may be linked to a variety of pre-mRNA maturation events that use the phosphorylated CTD, including the coupled processes of pre-mRNA 3'-end formation and transcription termination.

The WW domain is a protein module found in a wide range of signaling proteins. It is one of the smallest protein modules that folds as a monomer without disulfide bridges or cofactors. WW domains bind proteins containing short linear peptide motifs that are proline-rich or contain at least one proline. Although the WW domain was initially considered a 'cytoplasmic module', the proteins containing WW domains have also been localized in the cell nucleus. Moreover, these proteins have been documented to participate in co-activation of transcription and modulation of RNA polymerase II activity. The carboxy-terminal domain (CTD) of RNA polymerase II acts as an assembly platform for distinct WW domain-containing proteins that affect the function of the RNA polymerase II. The formation of complexes between CTD and WW domain-containing proteins is regulated by phosphorylation of the CTD. Since the CTD sequence is highly repetitive and a target of several post-translational modifications and conformational changes, it presents a unique structure capable of enormous molecular diversity. The WW domain has been implicated in several human diseases including Alzheimer's disease. The WW domain-containing iso-prolyl isomerase named Pin1, a protein known to be essential for cell cycle progression, was shown to be active in restoration of the microtubule-binding activity of Tau, a protein of neurofibrillar tangles found in the brains of Alzheimer's patients. It is the WW domain of Pin1 that interacts directly with Tau protein. In addition, the WW domain-containing adapter protein FE65 was shown to regulate processing of Alzheimer's amyloid precursor protein. It is expected that by understanding the details of the WW domain-mediated protein-protein interactions, we will be able to illuminate numerous signaling pathways which control certain aspects of transcription and cell cycle.

Gynoecia of the Arabidopsis mutant sty1-1 display abnormal style morphology and altered vascular patterning. These phenotypes, which are enhanced in the sty1-1 sty2-1 double mutant, suggest that auxin homeostasis or signalling might be affected by mutations in STY1 and STY2, both members of the SHI gene family. Chemical inhibition of polar auxin transport (PAT) severely affects the apical-basal patterning of the gynoecium, as do mutations in the auxin transport/signalling genes PIN1, PID and ETT. Here we show that the apical-basal patterning of sty1-1 and sty1-1 sty2-1 gynoecia is hypersensitive to reductions in PAT, and that sty1-1 enhances the PAT inhibition-like phenotypes of pin1-5, pid-8 and ett-1 gynoecia. Furthermore, we show that STY1 activates transcription of the flavin monooxygenase-encoding gene THREAD/YUCCA4, involved in auxin biosynthesis, and that changes in expression of STY1 and related genes lead to altered auxin homeostasis. Our results suggest that STY1 and related genes promote normal development of the style and affect apical-basal patterning of the gynoecium through regulation of auxin homeostasis.

Thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine initially identified in the culture supernatant of a thymic stromal cell line. Highly expressed in the epidermis in skin lesions of atopic dermatitis patients, TSLP was subsequently found to be a critical factor linking responses at interfaces between the body and environment (skin, airway, gut, ocular tissues, and so on) to Th2 responses. Recent studies have revealed that various cell types other than epithelial cells and epidermal keratinocytes (such as mast cells, airway smooth muscle cells, fibroblasts, dendritic cells, trophoblasts, and cancer or cancer-associated cells) also express TSLP. Environmental factors such as Toll-like receptor ligands, a Nod2 ligand, viruses, microbes, allergen sources, helminths, diesel exhaust, cigarette smoke, and chemicals trigger TSLP production. Proinflammatory cytokines, Th2-related cytokines, and IgE also induce or enhance TSLP production, indicating cycles of amplification. Skin barrier injury, increased epidermal endogenous protease activity, and less epidermal Notch signaling, all of which have been reported in atopic dermatitis, and keratinocyte-specific loss of retinoid X receptors and treatment of skin with agonists for vitamin D receptor in mice induce TSLP production, Th2 response, or atopic dermatitis-like inflammation. The transcription factors NF-κB and AP-1, nuclear receptors, single nucleotide polymorphisms, microRNAs, and the peptidyl-proryl isomerase Pin1 regulate TSLP mRNA expression transcriptionally or posttranscriptionally. This review focuses on events upstream of TSLP production, which is critical in allergic diseases and important in other TSLP-related disorders i.e. production sites, cellular sources, environmental and endogenous triggers and regulatory factors, and regulatory mechanisms of gene expression.

Cyclin E, an activator of cyclin-dependent kinase 2 (Cdk2), is targeted for proteasomal degradation by phosphorylation-dependent multiubiquitylation via the ubiquitin ligase SCF(hCdc4). SCF ubiquitin ligases are composed of a core of conserved subunits and one variable subunit (an F box protein) involved in substrate recognition. We show here that multiubiquitylation of cyclin E requires the sequential function of two distinct splice variant isoforms of the F box protein hCdc4 known as alpha and gamma. SCF(hCdc4alpha) binds a complex containing cyclin E, Cdk2, and the prolyl cis/trans isomerase Pin1 and promotes the activity of Pin1 without directly ubiquitylating cyclin E. However, due to the action of this SCF(hCdc4alpha)-Pin1 complex, cyclin E becomes an efficient ubiquitylation substrate of SCF(hCdc4gamma). Furthermore, in the context of Cdc4alpha and cyclin E, mutational data suggest that Pin1 isomerizes a noncanonical proline-proline bond, with the possibility that Cdc4alpha may serve as a cofactor for altering the specificity of Pin1.

It is unclear how the Warburg effect that exemplifies enhanced glycolysis in the cytosol is coordinated with suppressed mitochondrial pyruvate metabolism. We demonstrate here that hypoxia, EGFR activation, and expression of K-Ras G12V and B-Raf V600E induce mitochondrial translocation of phosphoglycerate kinase 1 (PGK1); this is mediated by ERK-dependent PGK1 S203 phosphorylation and subsequent PIN1-mediated cis-trans isomerization. Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex. This reduces mitochondrial pyruvate utilization, suppresses reactive oxygen species production, increases lactate production, and promotes brain tumorigenesis. Furthermore, PGK1 S203 and PDHK1 T338 phosphorylation levels correlate with PDH S293 inactivating phosphorylation levels and poor prognosis in glioblastoma patients. This work highlights that PGK1 acts as a protein kinase in coordinating glycolysis and the tricarboxylic acid (TCA) cycle, which is instrumental in cancer metabolism and tumorigenesis.

Auxin is an essential regulator for plant development. To elucidate the mechanisms by which auxin regulates plant development, we isolated an Arabidopsis mutant naked pins in yuc mutants 1 (npy1) that develops pin-like inflorescences and fails to initiate any flowers in yuc1 yuc4, a background that is defective in auxin biosynthesis. The phenotypes of npy1 yuc1 yuc4 triple mutants closely resemble those of Arabidopsis mutants pin-formed1 (pin1), pinoid (pid), and monopteros (mp), which are defective in either auxin transport or auxin signaling. NPY1 belongs to a large family of proteins and is homologous to NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3), a BTB/POZ protein that regulates phototropic responses along with the protein kinase PHOT1 (Phototropin 1). We demonstrate that NPY1 works with the protein kinase PID, which is homologous to PHOT1, to regulate auxin-mediated plant development. The npy1 pid double mutants fail to form any cotyledons, a phenotype that is also observed in yuc1 yuc4 pid triple mutants. Interestingly, both auxin-regulated organogenesis and phototropic responses require an auxin response factor (ARF). Disruption of ARF7/NPH4 leads to nonphototropic hypocotyls and arf5/mp forms pin-like inflorescences. Whereas the PHOT1/NPH3 pathway is regulated by light, our data suggest that the PID/NPY1 pathway may be regulated by auxin synthesized by the YUC flavin monooxygenases. Our findings put YUCs, PID, and NPY1 into a genetic framework for further dissecting the mechanisms of auxin action in plant development.

Cancer and Alzheimer's disease (AD) are two common disorders for which the final pathophysiological mechanism is not yet clearly defined. In a prospective longitudinal study we have previously shown an inverse association between AD and cancer, such that the rate of developing cancer in general with time was significantly slower in participants with AD, while participants with a history of cancer had a slower rate of developing AD. In cancer, cell regulation mechanisms are disrupted with augmentation of cell survival and/or proliferation, whereas conversely, AD is associated with increased neuronal death, either caused by, or concomitant with, beta amyloid (Abeta) and tau deposition. The possibility that perturbations of mechanisms involved in cell survival/death regulation could be involved in both disorders is discussed. Genetic polymorphisms, DNA methylation or other mechanisms that induce changes in activity of molecules with key roles in determining the decision to "repair and live"- or "die" could be involved in the pathogenesis of the two disorders. As examples, the role of p53, Pin1 and the Wnt signaling pathway are discussed as potential candidates that, speculatively, may explain inverse associations between AD and cancer.

Breast cancer is a heterogeneous disease that progresses to the critical hallmark of metastasis. In the present study, we show that the High Mobility Group A1 (HMGA1) protein plays a fundamental role in this process in basal-like breast cancer subtype. HMGA1 knockdown induces the mesenchymal to epithelial transition and dramatically decreases stemness and self-renewal. Notably, HMGA1 depletion in basal-like breast cancer cell lines reduced migration and invasion in vitro and the formation of metastases in vivo. Mechanistically, HMGA1 activated stemness and key migration-associated genes which were linked to the Wnt/beta-catenin, Notch and Pin1/mutant p53 signalling pathways. Moreover, we identified a specific HMGA1 gene expression signature that was activated in a large subset of human primary breast tumours and was associated with poor prognosis. Taken together, these data provide new insights into the role of HMGA1 in the acquisition of aggressive features in breast cancer.

The dynamic spatial and temporal distribution of the crucial plant signaling molecule auxin is achieved by feedback coordination of auxin signaling and intercellular auxin transport pathways. Developmental roles of auxin have been attributed predominantly to its effect on transcription; however, an alternative pathway involving AUXIN BINDING PROTEIN1 (ABP1) has been proposed to regulate clathrin-mediated endocytosis in roots and Rho-like GTPase (ROP)-dependent pavement cell interdigitation in leaves. In this study, we show that ROP6 and its downstream effector RIC1 regulate clathrin association with the plasma membrane for clathrin-mediated endocytosis, as well as for its feedback regulation by auxin. Genetic analysis revealed that ROP6/RIC1 acts downstream of ABP1 to regulate endocytosis. This signaling circuit is also involved in the feedback regulation of PIN-FORMED 1 (PIN1) and PIN2 auxin transporters activity (via its constitutive endocytosis) and corresponding auxin transport-mediated processes, including root gravitropism and leave vascular tissue patterning. Our findings suggest that the signaling module auxin-ABP1-ROP6/RIC1-clathrin-PIN1/PIN2 is a shared component of the feedback regulation of auxin transport during both root and aerial development.

The phytohormone auxin is a major determinant of plant growth and differentiation. Directional auxin transport and auxin responses are required for proper embryogenesis, organ formation, vascular development, and tropisms. Members of several protein families, including the PIN auxin efflux facilitators, have been implicated in auxin transport; however, the regulation of auxin transport by signaling proteins remains largely unexplored. We have studied a family of four highly homologous AGC protein kinases, which we designated the D6 protein kinases (D6PKs). We found that d6pk mutants have defects in lateral root initiation, root gravitropism, and shoot differentiation in axillary shoots, and that these phenotypes correlate with a reduction in auxin transport. Interestingly, D6PK localizes to the basal (lower) membrane of Arabidopsis root cells, where it colocalizes with PIN1, PIN2 and PIN4. D6PK and PIN1 interact genetically, and D6PK phosphorylates PIN proteins in vitro and in vivo. Taken together, our data show that D6PK is required for efficient auxin transport and suggest that PIN proteins are D6PK phosphorylation targets.

Phosphorylation of proteins on serine or threonine residues preceding proline is a key signalling mechanism in diverse physiological and pathological processes. Pin1 (peptidyl-prolyl cis-trans isomerase) is the only enzyme known that can isomerise specific Ser/Thr-Pro peptide bonds after phosphorylation and regulate their conformational changes with high efficiency. These Pin1-catalysed conformational changes can have profound effects on phosphorylation signalling by regulating a spectrum of target activities. Interestingly, Pin1 deregulation is implicated in a number of diseases, notably ageing and age-related diseases, including cancer and Alzheimer disease. Pin1 is overexpressed in most human cancers; it activates numerous oncogenes or growth enhancers and also inactivates a large number of tumour suppressors or growth inhibitors. By contrast, ablation of Pin1 prevents cancer, but eventually leads to premature ageing and neurodegeneration. Consistent with its neuroprotective role, Pin1 has been shown to be inactivated in neurons of patients with Alzheimer disease. Therefore, Pin1-mediated phosphorylation-dependent prolyl isomerisation represents a unique signalling mechanism that has a pivotal role in the development of human diseases, and might offer an attractive new diagnostic and therapeutic target.

Pin1 is a phospho-specific prolyl isomerase that regulates numerous key signaling molecules and whose deregulation contributes to disease notably cancer. However, since prolyl isomerases are often believed to be constitutively active, little is known whether and how Pin1 catalytic activity is regulated. Here, we identify death-associated protein kinase 1 (DAPK1), a known tumor suppressor, as a kinase responsible for phosphorylation of Pin1 on Ser71 in the catalytic active site. Such phosphorylation fully inactivates Pin1 catalytic activity and inhibits its nuclear location. Moreover, DAPK1 inhibits the ability of Pin1 to induce centrosome amplification and cell transformation. Finally, Pin1 pSer71 levels are positively correlated with DAPK1 levels and negatively with centrosome amplification in human breast cancer. Thus, phosphorylation of Pin1 Ser71 by DAPK1 inhibits its catalytic activity and cellular function, providing strong evidence for an essential role of the Pin1 enzymatic activity for its cellular function.

Pyruvate kinase is a rate-limiting glycolytic enzyme. The PKM1 and PKM2 isoforms result from mutually exclusive alternative splicing of the PKM pre-mRNA. PKM2 rather than PKM1 regulates the Warburg effect and tumorigenesis by poorly understood mechanisms. Emerging evidence has revealed that ERK1/2 phosphorylates PKM2, but not PKM1, leading to PIN1-dependent cis-trans isomerization and conversion of PKM2 from a tetramer to a monomer. Monomeric PKM2 translocates into the nucleus, where it functions as a histone kinase and upregulates the expression of c-Myc and cyclin D1, thereby promoting the Warburg effect and cell cycle progression, respectively. Thus, nuclear PKM2 is essential for tumorigenesis and may serve as a target for treating human cancer.