Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells.
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.
Wimmer-Kleikamp
Sabine H
SH
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
Nievergall
Eva
E
Gegenbauer
Kristina
K
Adikari
Samantha
S
Mansour
Mariam
M
Yeadon
Trina
T
Boyd
Andrew W
AW
Patani
Neill R
NR
Lackmann
Martin
M
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
D036386:Ephrin-A5; D036342:Ephrins; D036121:Receptor, EphA3; D036081:Receptors, Eph Family; D017027:Protein Tyrosine Phosphatases