المؤلفون: Yaron, Tomer M, Heaton, Brook E, Levy, Tyler M, Johnson, Jared L, Jordan, Tristan X, Cohen, Benjamin M, Kerelsky, Alexander, Lin, Ting-Yu, Liberatore, Katarina M, Bulaon, Danielle K, Van Nest, Samantha J, Koundouros, Nikos, Kastenhuber, Edward R, Mercadante, Marisa N, Shobana-Ganesh, Kripa, He, Long, Schwartz, Robert E, Chen, Shuibing, Weinstein, Harel, Elemento, Olivier, Piskounova, Elena, Nilsson-Payant, Benjamin E, Lee, Gina, Trimarco, Joseph D, Burke, Kaitlyn N, Hamele, Cait E, Chaparian, Ryan R, Harding, Alfred T, Tata, Aleksandra, Zhu, Xinyu, Tata, Purushothama Rao, Smith, Clare M, Possemato, Anthony P, Tkachev, Sasha L, Hornbeck, Peter V, Beausoleil, Sean A, Anand, Shankara K, Aguet, François, Getz, Gad, Davidson, Andrew D, Heesom, Kate, Kavanagh-Williamson, Maia, Matthews, David A, tenOever, Benjamin R, Cantley, Lewis C, Blenis, John, Heaton, Nicholas S

المصدر: Science Signaling. 15(757)

مصطلحات موضوعية: Pneumonia & Influenza, Prevention, Immunization, Biotechnology, Vaccine Related, Lung, Emerging Infectious Diseases, Infectious Diseases, Infection, Good Health and Well Being, Animals, Humans, SARS-CoV-2, Phosphorylation, COVID-19, Glycogen Synthase Kinase 3, Virus Replication, Nucleocapsid Proteins, Nucleocapsid, Serine, Threonine, Mammals, Protein Serine-Threonine Kinases, Biochemistry and Cell Biology

الوصف: Multiple coronaviruses have emerged independently in the past 20 years that cause lethal human diseases. Although vaccine development targeting these viruses has been accelerated substantially, there remain patients requiring treatment who cannot be vaccinated or who experience breakthrough infections. Understanding the common host factors necessary for the life cycles of coronaviruses may reveal conserved therapeutic targets. Here, we used the known substrate specificities of mammalian protein kinases to deconvolute the sequence of phosphorylation events mediated by three host protein kinase families (SRPK, GSK-3, and CK1) that coordinately phosphorylate a cluster of serine and threonine residues in the viral N protein, which is required for viral replication. We also showed that loss or inhibition of SRPK1/2, which we propose initiates the N protein phosphorylation cascade, compromised the viral replication cycle. Because these phosphorylation sites are highly conserved across coronaviruses, inhibitors of these protein kinases not only may have therapeutic potential against COVID-19 but also may be broadly useful against coronavirus-mediated diseases.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/44d513ncTest

المؤلفون: Ludwig, David S, Aronne, Louis J, Astrup, Arne, de Cabo, Rafael, Cantley, Lewis C, Friedman, Mark I, Heymsfield, Steven B, Johnson, James D, King, Janet C, Krauss, Ronald M, Lieberman, Daniel E, Taubes, Gary, Volek, Jeff S, Westman, Eric C, Willett, Walter C, Yancy, William S, Ebbeling, Cara B

المصدر: American Journal of Clinical Nutrition. 114(6)

مصطلحات موضوعية: Prevention, Obesity, Nutrition, Cancer, Cardiovascular, Oral and gastrointestinal, Metabolic and endocrine, Stroke, Affordable and Clean Energy, Carbohydrates, Dietary Carbohydrates, Dietary Fats, Energy Intake, Energy Metabolism, Humans, Insulin, Pandemics, obesity, weight loss, dietary carbohydrate, energy balance, macronutrients, endocrinology, insulin, glucagon, incretins, scholarly discourse, Engineering, Medical and Health Sciences, Nutrition & Dietetics

الوصف: According to a commonly held view, the obesity pandemic is caused by overconsumption of modern, highly palatable, energy-dense processed foods, exacerbated by a sedentary lifestyle. However, obesity rates remain at historic highs, despite a persistent focus on eating less and moving more, as guided by the energy balance model (EBM). This public health failure may arise from a fundamental limitation of the EBM itself. Conceptualizing obesity as a disorder of energy balance restates a principle of physics without considering the biological mechanisms that promote weight gain. An alternative paradigm, the carbohydrate-insulin model (CIM), proposes a reversal of causal direction. According to the CIM, increasing fat deposition in the body-resulting from the hormonal responses to a high-glycemic-load diet-drives positive energy balance. The CIM provides a conceptual framework with testable hypotheses for how various modifiable factors influence energy balance and fat storage. Rigorous research is needed to compare the validity of these 2 models, which have substantially different implications for obesity management, and to generate new models that best encompass the evidence.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7wm5x0gjTest

المؤلفون: Rogava, Meri, Aprati, Tyler J, Chi, Wei-Yu, Melms, Johannes C, Hug, Clemens, Davis, Stephanie H, Earlie, Ethan M, Chung, Charlie, Deshmukh, Sachin K, Wu, Sharon, Sledge, George, Tang, Stephen, Ho, Patricia, Amin, Amit Dipak, Caprio, Lindsay, Gurjao, Carino, Tagore, Somnath, Ngo, Bryan, Lee, Michael J, Zanetti, Giorgia, Wang, Yiping, Chen, Sean, Ge, William, Melo, Luiza Martins Nascentes, Allies, Gabriele, Rösler, Jonas, Gibney, Goeffrey T, Schmitz, Oliver J, Sykes, Megan, Creusot, Rémi J, Tüting, Thomas, Schadendorf, Dirk, Röcken, Martin, Eigentler, Thomas K, Molotkov, Andrei, Mintz, Akiva, Bakhoum, Samuel F, Beyaz, Semir, Cantley, Lewis C, Sorger, Peter K, Meckelmann, Sven W, Tasdogan, Alpaslan, Liu, David, Laughney, Ashley M, Izar, Benjamin

مصطلحات موضوعية: cancer, diseases & disorders, Investigative techniques and equipment, CRISPR-Cas9, liver, metastasis, organs types and functions, organs, tissues, organelles, cell types and functions

الوصف: Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.

وصف الملف: application/pdf

العلاقة: https://repository.cshl.edu/id/eprint/41428/1/s43018-023-00704-x.pdfTest; Rogava, Meri, Aprati, Tyler J, Chi, Wei-Yu, Melms, Johannes C, Hug, Clemens, Davis, Stephanie H, Earlie, Ethan M, Chung, Charlie, Deshmukh, Sachin K, Wu, Sharon, Sledge, George, Tang, Stephen, Ho, Patricia, Amin, Amit Dipak, Caprio, Lindsay, Gurjao, Carino, Tagore, Somnath, Ngo, Bryan, Lee, Michael J, Zanetti, Giorgia, Wang, Yiping, Chen, Sean, Ge, William, Melo, Luiza Martins Nascentes, Allies, Gabriele, Rösler, Jonas, Gibney, Goeffrey T, Schmitz, Oliver J, Sykes, Megan, Creusot, Rémi J, Tüting, Thomas, Schadendorf, Dirk, Röcken, Martin, Eigentler, Thomas K, Molotkov, Andrei, Mintz, Akiva, Bakhoum, Samuel F, Beyaz, Semir, Cantley, Lewis C, Sorger, Peter K, Meckelmann, Sven W, Tasdogan, Alpaslan, Liu, David, Laughney, Ashley M, Izar, Benjamin (January 2024) Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation. Nature Cancer. ISSN 2662-1347 (Public Dataset)

الإتاحة: https://doi.org/10.1038/s43018-023-00704-xTest
https://repository.cshl.edu/id/eprint/41428Test/
https://repository.cshl.edu/id/eprint/41428/1/s43018-023-00704-x.pdfTest
https://www.ncbi.nlm.nih.gov/pubmed/38286827Test

المؤلفون: Zheng, Yuxiang, Lin, Ting-Yu, Lee, Gina, Paddock, Marcia N, Momb, Jessica, Cheng, Zhe, Li, Qian, Fei, Dennis L, Stein, Benjamin D, Ramsamooj, Shivan, Zhang, Guoan, Blenis, John, Cantley, Lewis C

المصدر: Cell. 175(6)

مصطلحات موضوعية: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Nutrition, Complementary and Integrative Health, Cancer, Carbon, Cytosol, Formates, HCT116 Cells, HeLa Cells, Humans, MCF-7 Cells, Methotrexate, Mitochondria, Mitochondrial Proteins, Neoplasm Proteins, Neoplasms, Tetrahydrofolate Dehydrogenase, Tetrahydrofolates, Hela Cells, folate, formate, metabolism, methotrexate, mitochondria, one-carbon, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences

الوصف: Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6bc6x1f8Test

المؤلفون: Triscott, Joanna, Reist, Matthias, Küng, Lukas, Moselle, Francielle C, Lehner, Marika, Gallon, John, Ravi, Archna, Arora, Gurpreet K, De Brot, Simone, Lundquist, Mark, Gallart-Ayala, Hector, Ivanisevic, Julijana, Piscuoglio, Salvatore, Cantley, Lewis C, Emerling, Brooke M, Rubin, Mark A

المصدر: Triscott, Joanna; Reist, Matthias; Küng, Lukas; Moselle, Francielle C; Lehner, Marika; Gallon, John; Ravi, Archna; Arora, Gurpreet K; De Brot, Simone; Lundquist, Mark; Gallart-Ayala, Hector; Ivanisevic, Julijana; Piscuoglio, Salvatore; Cantley, Lewis C; Emerling, Brooke M; Rubin, Mark A (2023). PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition. Science Advances, 9(5), eade8641. American Association for the Advancement of Science 10.1126/sciadv.ade8641

مصطلحات موضوعية: 610 Medicine & health

الوصف: Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P2. We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance.

وصف الملف: application/pdf

العلاقة: https://boris.unibe.ch/178285Test/

الإتاحة: https://doi.org/10.1126/sciadv.ade8641Test
https://boris.unibe.ch/178285/1/sciadv.ade8641.pdfTest
https://boris.unibe.ch/178285Test/

المؤلفون: Davidson, Shawn M, Schmidt, Daniel R, Heyman, Julia E, O'Brien, James P, Liu, Amy C, Israelsen, William J, Dayton, Talya L, Sehgal, Raghav, Bronson, Roderick T, Freinkman, Elizaveta, Mak, Howard H, Fanelli, Giuseppe Nicolò, Malstrom, Scott, Bellinger, Gary, Carracedo, Arkaitz, Pandolfi, Pier Paolo, Courtney, Kevin D, Jha, Abhishek, DePinho, Ronald A, Horner, James W, Thomas, Craig J, Cantley, Lewis C, Loda, Massimo, Vander Heiden, Matthew G

المساهمون: Massachusetts Institute of Technology. Department of Biology

المصدر: AACR Journals

الوصف: Abstract Altered metabolism helps sustain cancer cell proliferation and survival. Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (PKM2), which can support anabolic metabolism to support cell proliferation. However, Pkm2 expression is dispensable for the formation and growth of many cancers in vivo. Expression of pyruvate kinase isoform M1 (Pkm1) is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied than PKM2. To test how differential expression of pyruvate kinase isoforms affects cancer initiation and progression, we generated mice harboring a conditional allele of Pkm1 and crossed these mice, or those with a Pkm2 conditional allele, with a Pten loss-driven prostate cancer model. Pkm1 loss led to increased PKM2 expression and accelerated prostate cancer development, whereas Pkm2 deletion led to increased PKM1 expression and suppressed tumor progression. Metabolic profiling revealed altered nucleotide levels in tumors with high PKM1 expression, and failure of these tumors to progress was associated with DNA replication stress and senescence. Consistent with these data, a small molecule pyruvate kinase activator that mimics a high activity PKM1-like state suppressed progression of established prostate tumors. Analysis of human specimens showed PKM2 expression is retained in most human prostate cancers. Overall, this study uncovers a role for pyruvate kinase isoforms in prostate cancer initiation and progression, and argues that pharmacologic pyruvate kinase activation may be beneficial for treating prostate cancer. Significance: Differential expression of PKM1 and PKM2 impacts prostate tumorigenesis and suggests a potential therapeutic vulnerability in prostate cancer.

وصف الملف: application/pdf

العلاقة: Cancer Research; https://hdl.handle.net/1721.1/147020Test; Davidson, Shawn M, Schmidt, Daniel R, Heyman, Julia E, O'Brien, James P, Liu, Amy C et al. 2022. "Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma." Cancer Research, 82 (13).

الإتاحة: https://hdl.handle.net/1721.1/147020Test

المؤلفون: Johnson, Jared L., Yaron, Tomer M., Huntsman, Emily M., Kerelsky, Alexander, Song, Junho, Regev, Amit, Lin, Ting-Yu, Liberatore, Katarina, Cizin, Daniel M., Cohen, Benjamin M., Vasan, Neil, Ma, Yilun, Krismer, Konstantin, Torres Robles, Jaylissa, van de Kooij, Bert, van Vlimmeren, Anne E., Andrée-Busch, Nicole, Käufer, Norbert F., Dorovkov, Maxim V., Ryazanov, Alexey G., Takagi, Yuichiro, Kastenhuber, Edward R., Goncalves, Marcus D., Hopkins, Benjamin D., Elemento, Olivier, Taatjes, Dylan J., Maucuer, Alexandre, Yamashita, Akio, Degterev, Alexei, Uduman, Mohamed, Lu, Jingyi, Landry, Sean D., Zhang, Bin, Cossentino, Ian, Linding, Rune, Blenis, John, Hornbeck, Peter V., Turk, Benjamin E., Yaffe, Michael B., Cantley, Lewis C.

المساهمون: Biochemistry and Molecular Biology, School of Medicine

المصدر: PMC

مصطلحات موضوعية: Kinases, Cellular signalling networks, Bioinformatics, Phosphorylation

الوصف: Protein phosphorylation is one of the most widespread post-translational modifications in biology (1,2). With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes (3,4). For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible (3). Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.

وصف الملف: application/pdf

العلاقة: Nature; Johnson JL, Yaron TM, Huntsman EM, et al. An atlas of substrate specificities for the human serine/threonine kinome. Nature. 2023;613(7945):759-766. doi:10.1038/s41586-022-05575-3; https://hdl.handle.net/1805/36481Test

الإتاحة: https://doi.org/10.1038/s41586-022-05575-3Test
https://hdl.handle.net/1805/36481Test

المؤلفون: Jbara, Amina, Lin, Kuan-Ting, Stossel, Chani, Siegfried, Zahava, Shqerat, Haya, Amar-Schwartz, Adi, Elyada, Ela, Mogilevsky, Maxim, Raitses-Gurevich, Maria, Johnson, Jared L., Yaron, Tomer M., Ovadia, Ofek, Jang, Gun Ho, Danan-Gotthold, Miri, Cantley, Lewis C., Levanon, Erez Y., Gallinger, Steven, Krainer, Adrian R., Golan, Talia, Karni, Rotem

المصدر: Nature ; volume 617, issue 7959, page 147-153 ; ISSN 0028-0836 1476-4687

مصطلحات موضوعية: Multidisciplinary

الوصف: Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation is correlated with the dissemination of metastases 1–3 . Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression. De novo motif analysis of these events detected enrichment of motifs with high similarity to the RBFOX2 motif. Overexpression of RBFOX2 in a patient-derived xenograft (PDX) metastatic PDA cell line drastically reduced the metastatic potential of these cells in vitro and in vivo, whereas depletion of RBFOX2 in primary pancreatic tumour cell lines increased the metastatic potential of these cells. These findings support the role of RBFOX2 as a potent metastatic suppressor in PDA. RNA-sequencing and splicing analysis of RBFOX2 target genes revealed enrichment of genes in the RHO GTPase pathways, suggesting a role of RBFOX2 splicing activity in cytoskeletal organization and focal adhesion formation. Modulation of RBFOX2-regulated splicing events, such as via myosin phosphatase RHO-interacting protein (MPRIP), is associated with PDA metastases, altered cytoskeletal organization and the induction of focal adhesion formation. Our results implicate the splicing-regulatory function of RBFOX2 as a tumour suppressor in PDA and suggest a therapeutic approach for metastatic PDA.

الإتاحة: https://doi.org/10.1038/s41586-023-05820-3Test
https://www.nature.com/articles/s41586-023-05820-3.pdfTest
https://www.nature.com/articles/s41586-023-05820-3Test

المؤلفون: Paul, Swagatika, Sarraf, Shireen A., Nam, Ki Hong, Zavar, Leila, DeFoor, Nicole, Biswas, Sahitya Ranjan, Fritsch, Lauren E., Yaron, Tomer M., Johnson, Jared L., Huntsman, Emily M., Cantley, Lewis C., Ordureau, Alban, Pickrell, Alicia M.

المساهمون: National Institutes of Health

المصدر: Journal of Cell Biology ; volume 223, issue 2 ; ISSN 0021-9525 1540-8140

الوصف: Subcellular location and activation of Tank Binding Kinase 1 (TBK1) govern precise progression through mitosis. Either loss of activated TBK1 or its sequestration from the centrosomes causes errors in mitosis and growth defects. Yet, what regulates its recruitment and activation on the centrosomes is unknown. We identified that NAK-associated protein 1 (NAP1) is essential for mitosis, binding to and activating TBK1, which both localize to centrosomes. Loss of NAP1 causes several mitotic and cytokinetic defects due to inactivation of TBK1. Our quantitative phosphoproteomics identified numerous TBK1 substrates that are not only confined to the centrosomes but are also associated with microtubules. Substrate motifs analysis indicates that TBK1 acts upstream of other essential cell cycle kinases like Aurora and PAK kinases. We also identified NAP1 as a TBK1 substrate phosphorylating NAP1 at S318 to promote its degradation by the ubiquitin proteasomal system. These data uncover an important distinct function for the NAP1–TBK1 complex during cell division.

الإتاحة: https://doi.org/10.1083/jcb.202303082Test

المؤلفون: Lin, Ting-Yu, Ramsamooj, Shakti, Perrier, Tiffany, Liberatore, Katarina, Lantier, Louise, Vasan, Neil, Karukurichi, Kannan, Hwang, Seo-Kyoung, Kesicki, Edward A., Kastenhuber, Edward R., Wiederhold, Thorsten, Yaron, Tomer M., Huntsman, Emily M., Zhu, Mengmeng, Ma, Yilun, Paddock, Marcia N., Zhang, Guoan, Hopkins, Benjamin D., McGuinness, Owen, Schwartz, Robert E., Ersoy, Baran A., Cantley, Lewis C., Johnson, Jared L., Goncalves, Marcus D.

المصدر: Cell Reports ; volume 42, issue 12, page 113535 ; ISSN 2211-1247

مصطلحات موضوعية: General Biochemistry, Genetics and Molecular Biology

الإتاحة: https://doi.org/10.1016/j.celrep.2023.113535Test
https://api.elsevier.com/content/article/PII:S2211124723015474?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2211124723015474?httpAccept=text/plainTest