Browsing by Author "Blenis, John"

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    An atlas of substrate specificities for the human serine/threonine kinome
    (Springer Nature, 2023) 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.; Biochemistry and Molecular Biology, School of Medicine
    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.
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    Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease
    (American Thoracic Society, 2018-10-01) Han, MeiLan K.; Arteaga-Solis, Emilio; Blenis, John; Bourjeily, Ghada; Clegg, Deborah J.; DeMeo, Dawn; Duffy, Jeanne; Gaston, Ben; Heller, Nicola M.; Hemnes, Anna; Henske, Elizabeth Petri; Jain, Raksha; Lahm, Tim; Lancaster, Lisa H.; Lee, Joyce; Legato, Marianne J.; McKee, Sherry; Mehra, Reena; Morris, Alison; Prakash, Y. S.; Stampfli, Martin R.; Gopal-Srivastava, Rashmi; Laposky, Aaron D.; Punturieri, Antonello; Reineck, Lora; Tigno, Xenia; Clayton, Janine; Medicine, School of Medicine
    Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women's Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.