Prostate-Associated Gene 4 (PAGE4): Leveraging the Conformational Dynamics of a Dancing Protein Cloud as a Therapeutic Target

Salgia, Ravi; Jolly, Mohit Kumar; Dorff, Tanya B.; Lau, Clayton; Weninger, Keith; Orban, John; Kulkarni, Prakash

doi:10.3390/jcm7060156

Cited by 12 publications

(8 citation statements)

References 83 publications

(99 reference statements)

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“…Prostate-associated gene 4 (PAGE4) is an archetypal IDP implicated in human prostate cancer (PCa) [29,30] (Figure 1). PAGE4 binds to and potentiates the oncoprotein c-Jun, which heterodimerizes with members of the Fos family to form the Activator Protein-1 (AP-1) transcription factor complex [31,32].…”

Section: Introductionmentioning

confidence: 99%

Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level

et al. 2019

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Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences.

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Section: Introductionmentioning

confidence: 99%

Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level

et al. 2019

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“…This suggests that PAGE4 plays an important role in MPCa, since aberrant activation of the AR pathway is a critical step in the progression to mCRPC after androgen ablation therapy. Loss of PAGE4 in MPCa might result in activation of the AR signaling pathway, resulting in resistance to androgen-derivation therapy in men with MPCa [40,41]. However, as we recently demonstrated the role of PAGE4 in mCRPC is dependent on intratumor heterogeneity and downregulating the activity of the AR pathway depends on the co-expression and PAGE4 phosphorylation by HIPK1 and CLK2 that either potentiate or attenuate the effects on the AR pathway, respectively [42].…”

Section: Discussionmentioning

confidence: 96%

Cancer/Testis Antigens Differentially Expressed in Prostate Cancer: Potential New Biomarkers and Targets for Immunotherapies

Kagohara

Carleton

Takahashi

et al. 2019

Preprint

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Current clinical tests for prostate cancer (PCa), such as the PSA test, are not fully capable of discerning patients that are highly likely to develop metastatic prostate cancer (MPCa). Hence, more accurate prediction tools are needed to provide treatment strategies that are focused on the different risk groups. Cancer/testis antigens (CTAs) are expressed during embryonic development and present aberrant expression in cancer making them ideal tumor specific biomarkers. Here, the potential use of a panel of CTAs as a biomarker for PCa detection as well as metastasis prediction is explored. We initially identified eight CTAs (CEP55, NUF2, PAGE4, PBK, RQCD1, SPAG4, SSX2 and TTK) that are differentially expressed in MPCa when compared to local disease and used this panel to compare the gene and protein expression profiles in paired PCa and normal adjacent prostate tissue. We identified differential expression of all eight CTAs at the protein level when comparing 80 paired samples of PCa and the adjacent non-cancer tissue. Using multiple logistic regression we also show that a panel of these CTAs present high accuracy to discriminate normal from tumor samples. In summary, this study provides evidence that a panel of CTAs, differentially expressed in aggressive PCa, is a potential biomarker for diagnosis and prognosis to be used in combination with the current clinically available tools and is also a potential target for immunotherapy development. PRÉCISA panel of eight cancer/testis antigens aberrantly expressed in prostate cancer presents high accuracy to discriminate local from metastatic tumors. This signature includes potential biomarker and immunotherapy targets for aggressive prostate cancer. expression profiles; the next step is to evaluate the expression of CEP55, NUF2, PAGE4, PBK, RQCD1, SPAG4, SSX2 and TTK in larger cohorts with follow-up data right from screening to the development of MPCa.Also, the development of less invasive approaches (liquid biopsies) to measure CTAs expression in circulating tumor cells, and even the presence of antibodies against these immunogenic biomarkers would be beneficial for early detection of primary tumors as well as metastasis prediction.

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“…IDR therapeutic relevance is corroborated by the fact that many oncogenic molecules involved in signaling are enriched in IDRs. Importantly, IDRs have been confirmed in many cancer‐associated proteins including p53, BRACA1, PAGE4, and PTEN and successful attempts have been made to target these regions. For example, a small molecule inhibitor was used to lock the normally dynamic IDR in the MYC protein in a static conformation that was unable to bind MAX, thereby preventing its oncogenic signaling .…”

Section: Discussionmentioning

confidence: 99%

Presence and structure‐activity relationship of intrinsically disordered regions across mucins

et al. 2020

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Abbreviations: AMOP, adhesion-associated domain in MUC4 and other proteins domain; CH, charge hydropathy; D 2 P 2 , database of disordered protein predictions; ECM, extracellular matrix; EGF, epidermal growth factor-like domain; IDP, intrinsically disordered protein; IDR, intrinsically disordered region; MoRF, molecular recognition feature; NIDO, nidogen-like domain; PPI, protein-protein interaction; PTM, posttranslational modification; PTS sequence, proline, threonine and serine sequence; SEA, sea-urchin sperm protein enterokinase and agrin module; TM, transmembrane; VNTR, variable number of tandem repeat domain; vWD, von Willebrand factor D domain. AbstractMany members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion. The large size and extensive glycosylation present challenges to study the mucin structure using traditional methods, including crystallography. We offer the hypothesis that the functional versatility of mucins may be attributed to the presence of intrinsically disordered regions (IDRs) that provide dynamism and flexibility and that the IDRs offer potential therapeutic targets. Herein, we examined the links between the mucin structure and function based on IDRs, posttranslational modifications (PTMs), and potential impact on their interactome. Using sequence-based bioinformatics tools, we observed that mucins are predicted to be moderately (20%-40%) to highly (>40%) disordered and many conserved mucin domains could be disordered. Phosphorylation sites overlap with IDRs throughout the mucin sequences. Additionally, the majority of predicted O-and N-glycosylation sites in the tandem repeat regions occur within IDRs and these IDRs contain a large number of functional motifs, that is, molecular recognition features (MoRFs), which directly influence protein-protein interactions (PPIs).This investigation provides a novel perspective and offers an insight into the complexity and dynamic nature of mucins. K E Y W O R D Sintrinsically disordered protein, glycoprotein, protein-protein interaction, protein structure 1940 | CARMICHEAL Et AL.

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Prostate-Associated Gene 4 (PAGE4): Leveraging the Conformational Dynamics of a Dancing Protein Cloud as a Therapeutic Target

Cited by 12 publications

References 83 publications

Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level

Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level

Cancer/Testis Antigens Differentially Expressed in Prostate Cancer: Potential New Biomarkers and Targets for Immunotherapies

Presence and structure‐activity relationship of intrinsically disordered regions across mucins

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