The Role of Eph Receptor Tyrosine Kinases and Ephrin Ligands in Hematopoietic Cell Development and Function

Eph receptor tyrosine kinases and their ligands, the ephrins, appear to lie functionally at the interface between pattern formation and morphogenesis. We review the role of Eph and ephrin signalling in the formation of segmented structures, in the control of axon guidance and cell migration and in the development of the vasculature. We address the question of how the specificity of response is achieved and discuss the specificity of ephrin-Eph interactions and the significance of structural domains in Eph receptors.

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Eph Receptor Tyrosine Kinases and Ephrin Ligands Are Epigenetically Inactivated in Acute Lymphoblastic Leukemia and Are Potential New Tumor Suppressor Genes in Human Leukemia.

Blood ◽

10.1182/blood.v110.11.2128.2128 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2128-2128 ◽

Cited By ~ 1

Author(s):

Shao-qing Kuang ◽

Zhi-Hong Fang ◽

Gonzalo Lopez ◽

Weigang Tong ◽

Hui Yang ◽

...

Keyword(s):

Dna Methylation ◽

Cell Lines ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Leukemia Cell ◽

Human Leukemia ◽

Eph Receptor ◽

Leukemia Cell Lines ◽

Ephrin Ligands ◽

Aberrant Dna Methylation

Abstract The Eph (erythroprotein-producing hepatoma amplified sequence) family receptor tyrosine kinases and their ephrin ligands (ephrins) are involved in a variety of functions in normal cell development and cancer. We have identified several members of this family as potential targets of aberrant DNA methylation using Methylated CpG Island Amplification (MCA) / DNA promoter microarray technology. This is of importance as there are no prior reports of potential Eph receptor or Ephrin epigenetic inactivation in human leukemia. To further investigate the role of Eph receptor and ephrin family genes in leukemia, we have analyzed their DNA methylation status in a panel of 23 leukemia cell lines and 65 primary ALL patient samples. Aberrant DNA methylation of 9 of these genes (EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3) was detected in multiple leukemia cell lines but not in normal samples by bisulfite pyrosequencing. In ALL patient samples, the frequencies of DNA methylation detected in the promoter regions of these genes ranged from 23% to 87% for EPHA4, EPHA5, EPHA6, EPHB2, EPHB3, EPHB4, EphrinA5, Ephrin B2, and EphrinB3. Expression analysis of 3 of these genes (EPHA5, EPHB4 and Ephrin B2) in leukemia cell lines by real-time PCR further confirmed methylation associated gene silencing. Treatment of methylated/silenced cell lines with DNA methyltransferase inhibitor 5′-aza-2′-deoxycytidine resulted in gene re-expression. Forced overexpression of EPHB4 using a lentivirus transduction system in Raji cell lines resulted in decreased cell proliferation and adhesion-independent cell growth, as well as in an increase in staurosporine induction of apoptosis. In addition, EPHB4 overexpression resulted in a significant downregulation of phosphorylated Akt pathway but had no effect on mitogen-activated protein kinase pathway. In summary, we describe for the first time the epigenetic suppression of Ephrin receptors and their ligands in human leukemia, indicating that these genes may be potential tumor suppressors in leukemia. Targeting of these pathways may result in the development of new potential therapies and biomarkers for patients with ALL.

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Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by EphB2

Molecular Biology of the Cell ◽

10.1091/mbc.e17-07-0450 ◽

2017 ◽

Vol 28 (24) ◽

pp. 3532-3541 ◽

Cited By ~ 5

Author(s):

Fumihiko Okumura ◽

Akiko Joo-Okumura ◽

Keisuke Obara ◽

Alexander Petersen ◽

Akihiko Nishikimi ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Tyrosine Kinases ◽

Kinase Activity ◽

Receptor Tyrosine Kinases ◽

Cancer Development ◽

Tyrosine Kinase Activity ◽

Eph Receptor ◽

Ephrin Ligands ◽

Dependent Cell ◽

Socs Box

Eph receptor tyrosine kinases and their ephrin ligands are overexpressed in various human cancers, including colorectal malignancies, suggesting important roles in many aspects of cancer development and progression as well as in cellular repulsive responses. The ectodomain of EphB2 receptor is cleaved by metalloproteinases (MMPs) MMP-2/MMP-9 and released into the extracellular space after stimulation by its ligand. The remaining membrane-associated fragment is further cleaved by the presenilin-dependent γ-secretase and releases an intracellular peptide that has tyrosine kinase activity. Although the cytoplasmic fragment is degraded by the proteasome, the responsible ubiquitin ligase has not been identified. Here, we show that SOCS box-containing protein SPSB4 polyubiquitinates EphB2 cytoplasmic fragment and that SPSB4 knockdown stabilizes the cytoplasmic fragment. Importantly, SPSB4 down-regulation enhances cell repulsive responses mediated by EphB2 stimulation. Altogether, we propose that SPSB4 is a previously unidentified ubiquitin ligase regulating EphB2-dependent cell repulsive responses.

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