title: Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells.
abstract: Signaling by Eph receptors and cell-surface ephrin ligands modulates adhesive cell properties and thereby coordinates cell movement and positioning in normal and oncogenic development. While cell contact-dependent Eph activation frequently leads to cell-cell repulsion, also the diametrically opposite response, cell-cell adhesion, is a probable outcome. However, the molecular principles regulating such disparate functions have remained controversial. We have examined cell-biologic mechanisms underlying this switch by analyzing ephrin-A5-induced cell-morphologic changes of EphA3-positive LK63 pre-B acute lymphoblastic leukemia cells. Their exposure to ephrin-A5 surfaces leads to a rapid conversion from a suspended/nonpolarized to an adherent/polarized cell type, a transition that relies on EphA3 functions operating in the absence of Eph-kinase signaling. Cell morphology change and adhesion of LK63 cells are effectively attenuated by endogenous protein tyrosine phosphatase (PTP) activity, whereby PTP inhibition and productive EphA3-phosphotyrosine signaling reverse the phenotype to nonadherent cells with a condensed cytoskeleton. Our findings suggest that Eph-associated PTP activities not only control receptor phosphorylation levels, but as a result switch the response to ephrin contact from repulsion to adhesion, which may play a role in the pathology of hematopoietic tumors.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
authors.forename: Sabine H
authors.initials: SH
authors.lastname: Wimmer-Kleikamp
authors.forename: Eva
authors.initials: E
authors.lastname: Nievergall
authors.forename: Kristina
authors.initials: K
authors.lastname: Gegenbauer
authors.forename: Samantha
authors.initials: S
authors.lastname: Adikari
authors.forename: Mariam
authors.initials: M
authors.lastname: Mansour
authors.forename: Trina
authors.initials: T
authors.lastname: Yeadon
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Boyd
authors.forename: Neill R
authors.initials: NR
authors.lastname: Patani
authors.forename: Martin
authors.initials: M
authors.lastname: Lackmann
mesh_terms: D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D016764:Cell Polarity; D048430:Cell Shape; D036386:Ephrin-A5 / Q000502:physiology; D036342:Ephrins / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D036121:Receptor, EphA3 / Q000502:physiology; D036081:Receptors, Eph Family / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D036386:Ephrin-A5; D036342:Ephrins; D036121:Receptor, EphA3; D036081:Receptors, Eph Family; D017027:Protein Tyrosine Phosphatases