Protein kinases are important drug targets in human cancers, inflammation, and metabolic diseases. This report presents the structures of kinase domains for three cancer-associated protein kinases: ephrin receptor A2 (EphA2), focal adhesion kinase (FAK), and Aurora-A. The expression profiles of EphA2, FAK, and Aurora-A in carcinomas suggest that inhibitors of these kinases may have inherent potential as therapeutic agents. The structures were determined from crystals grown in nanovolume droplets, which produced high-resolution diffraction data at 1.7, 1.9, and 2.3 A for FAK, Aurora-A, and EphA2, respectively. The FAK and Aurora-A structures are the first determined within two unique subfamilies of human kinases, and all three structures provide new insights into kinase regulation and the design of selective inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/s0969-2126(02)00907-3 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).
J Med Chem
May 2018
Department of Biological Chemistry & Molecular Pharmacology , Harvard Medical School, Boston , Massachusetts 02115 , United States.
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1.
View Article and Find Full Text PDFOverexpression of eIF4F components in meningiomas and suppression of meningioma cell growth by inhibiting translation initiation.
Exp Neurol
January 2018
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA. Electronic address:
Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation.
View Article and Find Full Text PDFPreclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases.
Gene
August 2015
Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address:
Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases.
View Article and Find Full Text PDFTargeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis.
Apoptosis
May 2015
Laboratory of Molecular Genetics and Virology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7 Gronostajowa St., 30-387, Kraków, Poland,
Gangliosides are a diverse group of sialic acid containing glycosphigolipids that are abundantly present in an outer plasma membrane of some cells. Biological roles of gangliosides and other lipids in cell fate regulation are being extensively studied. Gangliosides are well known to be involved in interactions between cells and in signal transduction to regulate growth, adhesion and motility.
View Article and Find Full Text PDF[Suppression of Aurora-A by RNA interference inhibits laryngeal cancer Hep-2 cell growth].
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi
January 2012
Department of Otorhinolaryngology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China.
Objective: To investigate the effects of knockdown of Aurora-A by RNA interference on laryngeal cancer Hep-2 cell growth in vitro and in vivo.
Methods: A plasmid containing siRNA against Aurora-A was constructed and transfected into human laryngeal cancer cell line Hep-2. Measurements included the CCK-8 assay for viability and proliferation, Transwell assay for invasion, colony formation assay for cell anchorage-independent growth.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!