Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression.
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.
Genander
Maria
M
Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden.
Halford
Michael M
MM
Xu
Nan-Jie
NJ
Eriksson
Malin
M
Yu
Zuoren
Z
Qiu
Zhaozhu
Z
Martling
Anna
A
Greicius
Gedas
G
Thakar
Sonal
S
Catchpole
Timothy
T
Chumley
Michael J
MJ
Zdunek
Sofia
S
Wang
Chenguang
C
Holm
Torbjörn
T
Goff
Stephen P
SP
Pettersson
Sven
S
Pestell
Richard G
RG
Henkemeyer
Mark
M
Frisén
Jonas
J
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
C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D019938:Cyclin D1; D036183:Receptor, EphB2