Article
Biochemistry & Molecular Biology
Nina Nelson, Adelia Razeto, Alessia Gilardi, Mira Graettinger, Johannes Kirchmair, Manfred Juecker
Summary: Phosphoinositides PtdIns(3,4,5)P-3 and PtdIns(3,4)P-2 act as second messengers in cancerogenesis, with their downstream signaling mediated through a complex network of phosphoinositide binding effector proteins and phosphatases. Experimental results demonstrate high affinity phosphoinositide binding for most proteins tested, with AKT1 showing the highest affinity among effector proteins and PTEN displaying the highest affinity among phosphatases.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Clinical Neurology
Chi-Jing Choong, Cesar Aguirre, Keita Kakuda, Goichi Beck, Hiroki Nakanishi, Yasuyoshi Kimura, Shuichi Shimma, Kei Nabekura, Makoto Hideshima, Junko Doi, Keiichi Yamaguchi, Kichitaro Nakajima, Tomoya Wadayama, Hideki Hayakawa, Kousuke Baba, Kotaro Ogawa, Toshihide Takeuchi, Shaymaa Mohamed Mohamed Badawy, Shigeo Murayama, Seiichi Nagano, Yuji Goto, Yohei Miyanoiri, Yoshitaka Nagai, Hideki Mochizuki, Kensuke Ikenaka
Summary: The functional loss of SYNJ1 leads to elevated levels of PIP3, which promotes the pathological aggregation of alpha Syn and increases the risk of developing Parkinson's disease. This relationship was confirmed through cellular and model organism experiments, as well as analysis of postmortem brain samples from PD patients. These findings suggest that PIP3 may be a promising target for interventions in Parkinson's disease.
ACTA NEUROPATHOLOGICA
(2023)
Article
Multidisciplinary Sciences
Nilmani Singh, Adriana Reyes-Ordonez, Michael A. Compagnone, Jesus F. Moreno Castillo, Benjamin J. Leslie, Taekjip Ha, Jie Chen
Summary: This study explores the specific interactions of human PH domain-containing proteins with PIPs and reveals unexpected lipid-binding specificity among these proteins. By analyzing the structural requirements and functional relevance of PIP binding, as well as using a prediction algorithm, the researchers demonstrate widespread PIP binding among human PH domains.
NATURE COMMUNICATIONS
(2021)
Article
Biochemical Research Methods
Michelle Palmieri, Bruno Catimel, Dmitri Mouradov, Anuratha Sakthianandeswaren, Eugene Kapp, Ching-Seng Ang, Nicholas A. Williamson, Cameron J. Nowell, Michael Christie, Jayesh Desai, Peter Gibbs, Antony W. Burgess, Oliver M. Sieber
Summary: The nuclear translocation of PI3K alpha regulates the subcellular levels of PtdIns(3,4,5)P3 in colorectal cancer cell lines, and 867 potential nuclear PtdIns(3,4,5)P3 effector proteins have been identified. These effector proteins are mainly involved in RNA metabolism and may play a role in modulating pre-mRNA splicing. These findings suggest that nuclear PI3K alpha signaling through PtdIns(3,4,5)P3 effector proteins is important for CRC development.
MOLECULAR & CELLULAR PROTEOMICS
(2023)
Article
Pharmacology & Pharmacy
Olivier Preynat-Seauve, Evelyne Bao-Vi Nguyen, Yvonne Westermaier, Margaux Heritier, Sebastien Tardy, Yves Cambet, Maxime Feyeux, Aurelie Caillon, Leonardo Scapozza, Karl-Heinz Krause
Summary: The study revealed that Phenazopyridine is a kinase inhibitor, impacting key kinases involved in neural differentiation and pain induction.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Cell Biology
Ryoko Sato-Nishiuchi, Masamichi Doiguchi, Nanami Morooka, Kiyotoshi Sekiguchi
Summary: Polydom is an extracellular matrix protein involved in lymphatic vessel development. In this study, it was found that Polydom directly binds to Tie1, a receptor in the Angiopoietin-Tie system, and promotes lymphatic endothelial cell migration. The PI3K/Akt pathway is involved in Polydom-induced LEC migration. These findings suggest that Polydom plays a crucial role in lymphatic vessel development through Tie1 and the PI3K/Akt pathway.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Cell Biology
Yanhua Zhang, Baoyu He, Dong Zhang, Yifan Zhang, Chengkun Chen, Wenye Zhang, Shiyi Yang, Meilian Yao, Gaoping Cui, Jun Gu, Ting Wang, Zhang Lin, Youben Fan, Zuquan Xiong, Yujun Hao
Summary: PI3K regulatory subunit p85 normally stabilizes and regulates catalytic subunit p110 in the cytoplasm. Recent studies reveal that p85 without p110 in the nucleus plays important roles in biological processes. However, the mechanisms of p85 translocation into the nucleus are still unclear. In this study, we describe the mechanism by which p850 translocates into the nucleus to promote ccRCC tumorigenesis. Phosphorylation of p850 at Y464 by FAK facilitates its nuclear translocation in the kidney through enhancing p850 binding to KPNA1. PIK3R2/p850 is highly expressed in ccRCC samples and is associated with overall survival of ccRCC patients. Nuclear, but not cytoplasmic, p850 functions as an oncogene by repressing RB1 expression and regulating the G1/S cell cycle transition. Nuclear p850 represses RB1 expression by stabilizing histone methyltransferase EZH1/EZH2 proteins. Lastly, the FAK inhibitor defactinib significantly suppresses tumor growth in ccRCC with high p850 Y464 levels.
Review
Biochemistry & Molecular Biology
Javier Torres-Jimenez, Victor Albarran-Fernandez, Javier Pozas, Maria San Roman-Gil, Jorge Esteban-Villarrubia, Alfredo Carrato, Adriana Rosero, Enrique Grande, Teresa Alonso-Gordoa, Javier Molina-Cerrillo
Summary: Urothelial carcinoma, one of the most prevalent types of cancer worldwide, is experiencing a paradigm shift in its therapeutic landscape with the development of different therapies. Increased knowledge of the pathogenesis and genetic alterations in urothelial carcinoma is also contributing to this transformation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Editorial Material
Genetics & Heredity
Ivona Aksentijevich
Summary: Immune responses require a delicate balance - too weak or too strong a response can cause issues. Spleen tyrosine kinase plays a crucial role in multiple signaling pathways, and its gain-of-function alterations can lead to various problems, including hypogammaglobulinemia and predisposition to B cell lymphoma.
Article
Immunology
Wei Wei, Mitchell J. J. Geer, Xinyi Guo, Igor Dolgalev, Neville E. E. Sanjana, Benjamin G. G. Neel
Summary: SHP2 acts as an upstream regulator of RAS activation. Through CRISPR/Cas9 screening, LZTR1, MAP4K5, SPRED2/STK40, and INPPL1 were identified as novel genes associated with SHP2 resistance. Understanding the mechanisms of SHP2 resistance and identifying potential combination therapies is important for overcoming drug resistance in cancer treatment.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Editorial Material
Immunology
Pin Li, Napoleone Ferrara
Summary: This study reveals the crosstalk between VEGF receptors in different organs and emphasizes the importance of VEGF receptor expression and interplay in vascular heterogeneity.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Manali Tilak, Jennifer Holborn, Laura A. New, Jasmin Lalonde, Nina Jones
Summary: Glioblastoma multiforme (GBM) is a deadly cancer with limited response to existing therapies. Subtypes of GBM with distinct genetic signatures show aberrant activation of signal transduction pathways. Current research focuses on understanding these molecular alterations to develop more efficient targeted therapies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Hua-jian Shan, Kun Jiang, Ming-zhi Zhao, Wen-jing Deng, Wen-hao Cao, Jia-jun Li, Ke-ran Li, Chang She, Wei-feng Luo, Jin Yao, Xiao-zhong Zhou, Dan Zhang, Cong Cao
Summary: This study demonstrated that Gai1/3 proteins mediate SCF/c-Kit-activated signaling and angiogenesis in endothelial cells. Knockdown or knockout of Gai1/3, as well as dominant negative mutations, attenuated SCF-induced activation of Akt-mTOR and Erk, as well as endothelial cell proliferation, migration, and capillary tube formation.
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Kaori Kanemaru, Yoshikazu Nakamura
Summary: Phospholipase C (PLC) metabolizes phosphatidylinositol 4,5-bisphosphate in the plasma membrane and generates inositol 1,4,5-trisphosphate and diacylglycerol, which regulate cellular functions. Mammalian PLC consists of six typical classes and one atypical class, and dysregulation of PLC activity is associated with various diseases. Therefore, the review focuses on the structure, activation mechanisms, and physiological functions of mammalian PLC.
Article
Chemistry, Medicinal
Robert K. Lesniak, R. Jeremy Nichols, Marcus Schonemann, Jing Zhao, Chandresh R. Gajera, Grace Lam, Khanh C. Nguyen, J. William Langston, Mark Smith, Thomas J. Montine
Summary: This study reports the discovery of a novel GS-LRRK2 kinase inhibitor compound capable of entering the brain, providing a promising starting point for the development of more brain penetrant compounds.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Kelechi Njoku, Amy E. Campbell, Bethany Geary, Michelle L. MacKintosh, Abigail E. Derbyshire, Sarah J. Kitson, Vanitha N. Sivalingam, Andrew Pierce, Anthony D. Whetton, Emma J. Crosbie
Summary: Endometrial cancer is the most common cancer of the female genital tract, and this study shows that plasma-based metabolites have the potential to detect the cancer early in women with a BMI >= 30 kg/m(2). Specific lipid metabolites, including phospholipids and sphingolipids, demonstrate good accuracy for detection, especially when combined in a diagnostic model.
Article
Multidisciplinary Sciences
Angelica Arioli, Arianna Dagliati, Bethany Geary, Niels Peek, Philip A. Kalra, Anthony D. Whetton, Nophar Geifman
Summary: OptiMissP is a dashboard designed to visually and qualitatively evaluate missing values in proteomic data and guide decision-making in handling missing values. It provides visual tools and exploration of different imputation methods to help researchers and clinicians determine study-specific strategies for addressing missing values. OptiMissP also considers biases in protein distributions related to imputation methods and helps balance information loss and noise introduced by different missingness thresholds.
Article
Oncology
Bethany Geary, Erin Peat, Sarah Dransfield, Natalie Cook, Fiona Thistlethwaite, Donna Graham, Louise Carter, Andrew Hughes, Matthew G. Krebs, Anthony D. Whetton
Summary: TARGET (tumour characterisation to guide experimental targeted therapy) aims to match cancer patients entering early phase clinical trials to the best treatment based on their genetics, reducing the need for recruiting more patients. The study developed a Wellness Score using blood samples to predict patient survival more accurately than traditional performance status measurements. This score showed promising results in predicting overall survival and warrants further evaluation in larger patient populations.
Article
Genetics & Heredity
Valentina Cipriani, Anna Tierney, John R. Griffiths, Verena Zuber, Panagiotis Sergouniotis, John R. W. Yates, Anthony T. Moore, Paul N. Bishop, Simon J. Clark, Richard D. Unwin
Summary: The study revealed that mutations at the complement factor H (CFH) locus may lead to elevated concentrations of circulating FHR proteins, which could be major drivers of AMD. These findings support the need for research into FHR protein modulation as a potential therapeutic avenue for AMD.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Oncology
Ammara Muazzam, Davide Chiasserini, Janet Kelsall, Nophar Geifman, Anthony D. Whetton, Paul A. Townsend
Summary: Prostate cancer is the third most common cancer in men globally. The PSA is the main protein biomarker used for diagnosis, staging, and monitoring, but it can lead to inaccurate diagnosis and overtreatment. Therefore, identifying novel biomarkers for prostate cancer can help improve the understanding of diagnosis and risk assessment.
Article
Cell Biology
Helene A. Fachim, Zohaib Iqbal, J. Martin Gibson, Ivona Baricevic-Jones, Amy E. Campbell, Bethany Geary, Akheel A. Syed, Antony Whetton, Handrean Soran, Rachelle P. Donn, Adrian H. Heald
Summary: After metabolic bariatric surgery, changes in inflammatory markers and circulating proteins were observed, with some proteins correlating with alterations in IL6, TNF alpha, and CRP. Further studies are required to elucidate the mechanisms by which MBS reduces low-grade inflammation.
Article
Multidisciplinary Sciences
Stella Pearson, Anthony D. Whetton, Andrew Pierce
Summary: Despite advances in precision medicine targeted therapies for cancer, the development of curative treatments remains challenging due to drug resistance in cancer stem cells. Chronic myeloid leukemia is a model for studying cancer stem cells and although targeted therapies have been developed, drug resistance remains a problem. New treatment strategies are needed to target other components within leukemia stem cells, either alone or in combination with existing therapies.
Article
Biochemical Research Methods
Nyasha Munjoma, Giorgis Isaac, Ammara Muazzam, Olivier Cexus, Fowz Azhar, Hardev Pandha, Anthony D. Whetton, Paul A. Townsend, Ian D. Wilson, Lee A. Gethings, Robert S. Plumb
Summary: Lipids are crucial in biological processes and their accurate measurement is essential for understanding diseases and human health. A high throughput LC-MS method was developed to screen over 2000 lipids in human plasma/serum, and it combines the advantages of global lipid analysis and targeted approaches.
JOURNAL OF PROTEOME RESEARCH
(2022)
Article
Archaeology
K. N. White, D. Chiasserini, R. Loynes, A. R. David, B. E. van Dongen, K. Drosou, R. Forshaw, S. Fraser, P. Causey-Freeman, J. Metcalfe, E. Murphy, M. Regan, P. J. Reimer, D. G. Tosh, A. Whetton, A. J. Freemont
Summary: Scientific examination of mummies provides insights into human ancestry, diet, disease, cultures, and societies. However, invasive methods have raised concerns. A minimally invasive approach using imaging techniques and biopsy sampling allows for the collection of valuable data without significant disturbance to the mummy. This study on Takabuti demonstrates the potential of such methods.
JOURNAL OF ARCHAEOLOGICAL SCIENCE-REPORTS
(2023)
Article
Oncology
Kelechi Njoku, Andrew Pierce, Bethany Geary, Amy E. Campbell, Janet Kelsall, Rachel Reed, Alexander Armit, Rachel Da Sylva, Liqun Zhang, Heather Agnew, Ivona Baricevic-Jones, Davide Chiasserini, Anthony D. Whetton, Emma J. Crosbie
Summary: This study aimed to identify urine-based proteomic signatures that can differentiate endometrial cancer patients from symptomatic controls. Through mass spectrometry and machine learning techniques, a 10-marker protein panel was discovered that accurately detected endometrial cancer. This study provides a potential urine-based detection tool for non-invasive endometrial cancer detection.
BRITISH JOURNAL OF CANCER
(2023)
Article
Oncology
Ammara Muazzam, Matt Spick, Olivier N. F. Cexus, Bethany Geary, Fowz Azhar, Hardev Pandha, Agnieszka Michael, Rachel Reed, Sarah Lennon, Lee A. Gethings, Robert S. Plumb, Anthony D. Whetton, Nophar Geifman, Paul A. Townsend
Summary: Despite ongoing research, effective tools for detection and monitoring of prostate cancer are still lacking. This study aims to identify non-invasive biomarkers that can complement PSA in clinical decision-making. Novel prostate cancer protein signatures were discovered using an advanced analytical technique, and the results were validated using a second cohort of patients. The study provides a proteomic signature that can enhance the diagnosis and risk assessment of localized prostate cancer.
Article
Multidisciplinary Sciences
Stella Pearson, Rognvald Blance, Fei Yan, Ya-Ching Hsieh, Bethany Geary, Fabio M. R. Amaral, Tim C. P. Somervaille, Kristina Kirschner, Anthony D. D. Whetton, Andrew Pierce
Summary: Myelofibrosis is a neoplasm that affects the bone marrow and results in reduced life quality and length. Existing drugs provide some benefit, but there is a need for new therapies to better treat myelofibrosis. By re-analyzing proteomic data, researchers identified CBL0137 as a potential drug to target Jak2 mutation-driven malignancies.
Meeting Abstract
Endocrinology & Metabolism
H. Fachim, Z. Iqbal, M. Gibson, I. Baricevic-Jones, A. Campbell, B. Geary, R. Donn, A. Syed, A. Whetton, H. Soran, A. Heald
Meeting Abstract
Endocrinology & Metabolism
Z. Iqbal, H. Fachim, M. Gibson, I. Baricevic-Jones, A. Campbell, B. Geary, R. Donn, A. Syed, A. Whetton, H. Soran, A. Heald