title: Cancer somatic mutations disrupt functions of the EphA3 receptor tyrosine kinase through multiple mechanisms.
abstract: The Eph receptor tyrosine kinases make up an important family of signal transduction molecules that control many cellular processes, including cell adhesion and movement, cell shape, and cell growth. All of these are important aspects of cancer progression, but the relationship between Eph receptors and cancer is complex and not fully understood. Genetic screens of tumor specimens from cancer patients have revealed somatic mutations in many Eph receptors. The most highly mutated Eph receptor is EphA3, but its functional role in cancer is currently not well established. Here we show that many EphA3 mutations identified in lung, colorectal, and hepatocellular cancers, melanoma, and glioblastoma impair kinase activity or ephrin ligand binding and/or decrease the level of receptor cell surface localization. These results suggest that EphA3 has ephrin- and kinase-dependent tumor suppressing activities, which are disrupted by somatic cancer mutations.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Lisabeth
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D018450:Disease Progression; D036384:Ephrin-A3 / Q000737:chemistry; D005353:Fibronectins / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D036121:Receptor, EphA3; D015398:Signal Transduction
chemical_list: D036384:Ephrin-A3; D005353:Fibronectins; D011494:Protein Kinases; C491718:EPHA3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3