title: Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression.
abstract: Signaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-oncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2 regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2 signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor suppressor function and identifies a pharmacological strategy to suppress adenoma growth.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Genander
authors.forename: Michael M
authors.initials: MM
authors.lastname: Halford
authors.forename: Nan-Jie
authors.initials: NJ
authors.lastname: Xu
authors.forename: Malin
authors.initials: M
authors.lastname: Eriksson
authors.forename: Zuoren
authors.initials: Z
authors.lastname: Yu
authors.forename: Zhaozhu
authors.initials: Z
authors.lastname: Qiu
authors.forename: Anna
authors.initials: A
authors.lastname: Martling
authors.forename: Gedas
authors.initials: G
authors.lastname: Greicius
authors.forename: Sonal
authors.initials: S
authors.lastname: Thakar
authors.forename: Timothy
authors.initials: T
authors.lastname: Catchpole
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chumley
authors.forename: Sofia
authors.initials: S
authors.lastname: Zdunek
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.forename: Torbjörn
authors.initials: T
authors.lastname: Holm
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Goff
authors.forename: Sven
authors.initials: S
authors.lastname: Pettersson
authors.forename: Richard G
authors.initials: RG
authors.lastname: Pestell
authors.forename: Mark
authors.initials: M
authors.lastname: Henkemeyer
authors.forename: Jonas
authors.initials: J
authors.lastname: Frisén
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D004848:Epithelium; D006801:Humans; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D036183:Receptor, EphB2 / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
chemical_list: C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D019938:Cyclin D1; D036183:Receptor, EphB2