title: Structures of an Eph receptor tyrosine kinase and its potential activation mechanism.
abstract: Eph receptor tyrosine kinases (RTKs) and their ephrin ligands play a crucial role in both physiological and pathophysiological processes, including tumourigenesis. A previous study of Eph RTKs established a regulatory role for the juxtamembrane segment (JMS) in kinase activation through the phosphorylation of two tyrosines within the JMS. Here, structures of EphA2 representing various activation states are presented. By determining the unphosphorylated inactive and phosphorylated active structures as well as an alternative conformation, conformational changes during kinase activation have been revealed. It is shown that phosphorylation of a tyrosine residue (Tyr772) in the activation loop without direct involvement of the JMS is sufficient to activate the EphA2 kinase. This mechanistic finding is in contrast to the mechanism of other Eph RTKs, such as EphB2, in which phosphorylation of the two JMS tyrosines initiates the dissociation of the JMS and triggers activation-loop phosphorylation for kinase activation. Furthermore, experiments demonstrate that the EphA2 substrate PTEN, a phosphatase that has been implicated in tumour suppression, acts to regulate the phosphorylation states of EphA2, exemplifying a unique reciprocal enzyme-substrate system. Based on these studies, it is therefore suggested that EphA2 may possess an alternate activation mechanism distinct from other Eph RTKs.
authors.affiliation: College of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Department of Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: College of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: College of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Biology, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Chin-Sang
authors.affiliation: College of Chemistry, Beijing Normal University, Beijing 100875, People's Republic of China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, 99 University Avenue, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Jia
mesh_terms: D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D036104:Receptor, EphA2 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D036104:Receptor, EphA2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Eph receptor tyrosine kinases; EphA2; PTEN; kinase activation; reciprocal enzyme–substrate system