Survey
The role of ephrins and Eph receptors in cancer

https://doi.org/10.1016/j.cytogfr.2004.09.002Get rights and content

Abstract

Eph receptors are the largest receptor tyrosine kinase family of transmembrane proteins with an extracellular domain capable of recognizing signals from the cells’ environment and influencing cell–cell interaction and cell migration. Ephrins are the ligands to Eph receptors and stimulate bi-directional signaling of the Eph/ephrin axis. Eph receptor and ephrin overexpression can result in tumorigenesis as related to tumor growth and survival and is associated with angiogenesis and metastasis in many types of human cancer. Recent data suggest that Eph/ephrin signaling could play an important role in the development of novel inhibition strategies and cancer treatments to potentially target this receptor tyrosine kinase and/or its ligand. A deeper understanding of the molecular basis for normal versus defective cell–cell interaction through the Eph/ephrin axis will enable the potential development of novel cancer treatments. This review emphasizes the biology of Eph/ephrin as well as the potential for novel targeted therapy through this pathway.

Introduction

Eph receptors were originally identified in the late 1980s in a human cDNA library screen for homologous sequences to the tyrosine kinase domain of the viral oncogene v-fps [1]. The Eph receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. RTKs are transmembrane proteins with an extracellular domain capable of recognizing signals from the cells’ environment and can influence the growth and survival of cells by acting directly on gene transcription or indirectly on the production of second messengers. Eph/ephrin signaling is an indirect way of modulating a variety of biological activities, including cell–cell interaction and cell migration. One of the important consequences of Eph receptors and ephrins is their role in tumorigenesis and metastatic potential as related to tumor growth and survival. Elevated Eph/ephrin expression is associated with angiogenesis and tumor vasculature in many types of human cancers, including breast, lung, and prostate cancers, melanoma, and leukemia. Eph receptors and their ephrin ligands have also been implicated in diverse developmental and neurological functions, including hindbrain development in vertebrates and tissue patterning. Recent data suggest that Eph/ephrin signaling could play an important role in the development of novel inhibition strategies and cancer treatments to potentially target this receptor tyrosine kinase and/or its ligand. This review will discuss Eph receptors and ephrins, focusing on their role in cancer, but is in no way meant to be a comprehensive source. We have referenced original and review articles where possible, and apologize in advance to our colleagues that we have not referenced all of the original literature that exists on this topic due to space constraints.

Section snippets

Structure

Receptor tyrosine kinases (RTKs) are transmembrane spanning receptor proteins which contain an extracellular ligand binding domain and a cytosolic domain with inherent tyrosine kinase activity. They include the receptors for several growth factors (such as EGF, PDGF, and FGF) and insulin and contain over 50 different members organized into at least 14 different subgroups based on their structural organization. Ligand binding to a receptor tyrosine kinase induces receptor autophosphorylation of

Bi-directional signaling

A special feature of ephrins and Eph receptors is the concept of bi-directional—reverse and forward—signaling. An Eph receptor can act as a ligand in the same way that an ephrin ligand can act as a receptor. Ephrin ligand binding induces Eph receptor ‘forward’ signaling, usually requiring tyrosine kinase domain activation and transduction of the signal into the receptor-expressing cell [6]. But ephrins can also result in ‘reverse’ signal transduction into the ephrin-expressing cell. For

Biological functions

The cellular responses to Eph receptor stimulation by their ephrin ligands are important in mediating a wide range of biological activities, including angiogenesis, cell segregation, and cell attachment, shape, and motility. As several of these processes are know to go awry during tumorigenesis and metastasis, Eph/ephrin signaling has been identified to play a role in many human cancers, such as lung, breast, and prostate cancers, as well as melanoma, and leukemia. Besides their proposed role

Amplification and alteration in cancer

Posttranslational phosphorylation of proteins is an important regulatory mechanism in cell function and interaction. Its modification and consequent receptor/ligand alteration is thus one of the many factors that might result in the transformation of normal cells into an invasive or metastatic tumor. Eph receptors and ephrins have been found to be both over- and under-expressed in various tumor types. Upon the identification of the first member of the Eph family, EphA1, breast, liver, lung, and

Lung cancer

According to the American Cancer Society, an estimated 173,770 new cases of lung and bronchus cancer are expected in 2004 and account for approximately 13% of all cancer diagnoses. Lung cancer continues to be the leading cause of cancer death in the United States (approximately 28%), with an estimated 160,440 deaths in 2004 [69]. Thus, it is critical to further study possible novel therapeutic approaches for this devastating illness. The role of Eph receptors and their ephrin ligands in lung

Therapeutic approaches to inhibiting the eph/ephrin axis

In order to further advance novel cancer treatment methods, studies have been directed toward investigating new opportunities for therapeutic molecular targeting. In order to inhibit the transformation of a healthy cell with normal Eph/ephrin expression into a primary tumor and consequently into a metastatic/invasive tumor, investigators have focused on cell growth, viability, and apoptosis, as well as various cytoskeletal signaling pathways leading to cell motility and proliferation as

Conclusion

We are still in the process of understanding the cellular and molecular mechanisms involved in Eph and ephrin interaction and signaling. Since their functions include such processes as angiogenesis in tumor tissue, we can introduce the prospect of these molecules becoming candidates for tumor prognostic markers and potential targets for therapeutic intervention in cancer. The current challenge is to fully understand the mechanisms that govern the functional effects of Eph receptors and ephrins

Acknowledgments

Patrick C. Ma is supported by the American Association for Cancer Research (AACR)-AstraZeneca-Cancer Research and Prevention Foundation Fellowship in Translational Lung Cancer Research; and American Cancer Society Institutional Research Grant (ACS IRG-58-004-44). Ravi Salgia is supported by Research Scholar Grant awarded by the American Cancer Society (RSG-02-244-02-CCE), NIH/NCI R01 Grant (R01 CA100750-01A1), and Institutional V-Foundation Award.

References (82)

  • R.H. Adams et al.

    The cytoplasmic domain of the ligand ephrin-B2 is required for vascular morphogenesis but not cranial neural crest migration

    Cell

    (2001)
  • A. Palmer et al.

    EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase

    Mol Cell

    (2002)
  • E. Ruoslahti

    Fibronectin and its integrin receptors in cancer

    Adv Cancer Res

    (1999)
  • R.O. Hynes

    Integrins: versatility, modulation, and signaling in cell adhesion

    Cell

    (1992)
  • G. Maulik et al.

    Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition

    Cytokine Growth Factor Rev

    (2002)
  • N.K. Noren et al.

    Eph receptor-ephrin bidirectional signals that target Ras and Rho proteins

    Cell Signal

    (2004)
  • R.S. Winning et al.

    EphA4 activity causes cell shape change and a loss of cell polarity in Xenopus laevis embryos

    Differentiation

    (2001)
  • G. Berclaz et al.

    Expression of the receptor protein tyrosine kinase myk-1/htk in normal and malignant mammary epithelium

    Biochem Biophys Res Commun

    (1996)
  • M. Dottori et al.

    Cloning and characterization of EphA3 (Hek) gene promoter: DNA methylation regulates expression in hematopoietic tumor cells

    Blood

    (1999)
  • B.P. Fox et al.

    Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application

    Biochem Biophys Res Commun

    (2004)
  • G. Zeng et al.

    High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia

    Am J Pathol

    (2003)
  • M. Koolpe et al.

    An ephrin mimetic peptide that selectively targets the EphA2 receptor

    J Biol Chem

    (2002)
  • H. Hirai et al.

    A novel putative tyrosine kinase receptor encoded by the eph gene

    Science

    (1987)
  • K. Kullander et al.

    Mechanisms and functions of Eph and ephrin signalling

    Nat Rev Mol Cell Biol

    (2002)
  • E.B. Pasquale

    Eph-ephrin promiscuity is now crystal clear

    Nat Neurosci

    (2004)
  • J.P. Himanen et al.

    Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling

    Nat Neurosci

    (2004)
  • Rudiger

    Eph/ephrin signaling in morphogenesis, neural development and plasticity

    Curr. Opin. Cell Biol.

    (2004)
  • E. Stein et al.

    Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses

    Genes Dev

    (1998)
  • S. Davis et al.

    Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity

    Science

    (1994)
  • T. Fuller et al.

    Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrin-B2 positive cells

    J Cell Sci

    (2003)
  • J. Eberhart et al.

    Ephrin-A5 exerts positive or inhibitory effects on distinct subsets of EphA4-positive motor neurons

    J Neurosci

    (2004)
  • J.P. Himanen et al.

    Crystal structure of an Eph receptor-ephrin complex

    Nature

    (2001)
  • N.W. Gale et al.

    Ephrins and their receptors: a repulsive topic?

    Cell Tissue Res

    (1997)
  • N. Carter et al.

    Ephrin-A1-induced cytoskeletal re-organization requires FAK and p130(cas)

    Nat Cell Biol

    (2002)
  • I.D. Lawrenson et al.

    Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling

    J Cell Sci

    (2002)
  • H. Luo et al.

    Cross-linking of EphB6 resulting in signal transduction and apoptosis in Jurkat cells

    J Immunol

    (2001)
  • N. Sharfe et al.

    Ephrin-A1 induces c-Cbl phosphorylation and EphA receptor down-regulation in T cells

    J Immunol

    (2003)
  • H. Miao et al.

    Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation

    Nat Cell Biol

    (2000)
  • H.H. Yu et al.

    Multiple signaling interactions of Abl and Arg kinases with the EphB2 receptor

    Oncogene

    (2001)
  • C.A. Cowan et al.

    The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals

    Nature

    (2001)
  • M. Dohn et al.

    Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis

    Oncogene

    (2001)
  • Cited by (298)

    • Receptor tyrosine kinases (RTKs): from biology to pathophysiology

      2023, Receptor Tyrosine Kinases in Neurodegenerative and Psychiatric Disorders
    View all citing articles on Scopus
    View full text