Eph–ephrin signalling in adult tissues and cancer

https://doi.org/10.1016/j.ceb.2008.01.011Get rights and content

Eph receptor tyrosine kinases and their ligands, the ephrins, play key roles in the regulation of migration and cell adhesion during development, thereby influencing cell fate, morphogenesis and organogenesis. Recent findings suggest that Eph signalling also controls the architecture and physiology of different tissues in the adult body under normal and pathological conditions such as cancer. A prime example is the intestinal epithelium where EphB–ephrinB interactions regulate both cell positioning and tumor progression. Here, we will review recent advances on the role of Eph–ephrin signalling in the intestine and other organs.

Introduction

Eph receptors constitute the largest subfamily of transmembrane tyrosine kinase receptors described to date, with 14 members identified in mammals. Their ligands, the ephrins, are membrane-anchored proteins which are grouped into two subclasses: type-A ephrins (ephrinA1–ephrinA6) which are attached to the cell surface through a glycosylphosphatidylinositol (GPI) anchor, and type-B ephrins (ephrinB1–ephrinB3) containing transmembrane and intracellular domains (Figure 1). Depending on their sequence similarity and on their affinity for ephrins, Eph receptors are also classified in two groups. In general, EphA receptors (EphA1–EphA10) bind ephrinAs and EphB receptors (EphB1–EphB6) bind ephrinBs, yet promiscuity in their binding specificities has been described for some members (reviewed in [1]). Upon cell-to-cell contact and ligand–receptor engagement, intracellular signalling is induced in a bidirectional fashion: ‘forward signalling’ starts in receptor-expressing cells, while ‘reverse signalling’ initiates in cells expressing the corresponding ligand (Figure 1) (reviewed in [2] and [3]).

Eph–ephrin signalling regulates a number of cellular events during embryonic development such as cell migration, repulsion versus adhesion, and cell-to-cell communication. Most of these responses are achieved through the ability of Eph–ephrin signalling to regulate actin cytoskeleton dynamics (reviewed in [2, 3, 4]). Here, we will discuss recent findings on the role that Eph–ephrin signalling plays in several adult tissues. Because of space constraints, we will not comment on its key functions in neural plasticity and regeneration of the adult nervous system (for comprehensive reviews on this topic please see refs. [4] and [5]).

Section snippets

Control of tissue architecture and cell positioning in the adult

The intestinal epithelium represents perhaps the best-known example of adult tissue architecture controlled by Eph–ephrin signalling. The innermost layer of the intestinal tube is a mono-stratified epithelium which is folded into millions of bag-shaped invaginations called crypts. At the base of each crypt reside a handful of exceptionally active stem cells which continuously regenerate the epithelium [6••]. Cell renewal is accomplished in a bottom-up fashion. Intestinal stem cells (ISCs)

Regulation of blood cell function

EphB signalling also plays an important role favouring thrombus growth and stability [17]. Thrombus formation initiates as a response to vascular injury, and involves platelet activation and aggregation as well as fibrin clot formation. EphA4, EphB1 and ephrinB1 are expressed on the surface of freely circulating resting platelets. Upon activation, integrin-dependent aggregation allows Eph–ephrin interaction between contacting platelets. Eph–ephrin signals induce the phosphorylation of integrin

Control of pancreas physiology

Communication between endocrine β cells in the pancreas is required to inhibit basal insulin secretion during fasting periods, as well as to enhance glucose-stimulated insulin release after food intake. EphA5 and its cognate ligand ephrinA5 are coexpressed in β cells. When blood glucose levels are low, forward signalling through EphA5 receptor prevents insulin release from secretory granules. Upon an increase in glucose concentration, EphA5 receptor is dephosphorylated. Under these conditions,

Eph signalling in tumorigenesis

Somatic mutations and epigenetic silencing of Eph genes have been found in several types of cancer (Table 1). Recent evidences suggest that Eph–ephrin signalling suppresses tumor progression yet, in some cases, Eph–ephrin interactions may also promote cancer growth depending on tumor type and context.

Discussion

Distinct combinations of Eph receptors and ephrin ligands are expressed in virtually every single tissue of the adult body. The findings summarized here indicate that Eph–ephrin signalling has widespread roles in establishing the complex cellular architecture of adult tissues and in regulating certain physiological functions such as hormone secretion or platelet aggregation. Future research will pinpoint specific roles for each receptor–ligand pair in particular organs yet redundancy,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to the authors of original manuscripts that have not been cited because of space limitations. We thank Elena Sancho for manuscript proof reading and suggestions. A.M.-S. holds a postdoctoral fellowship from Asociación Española Contra el Cáncer.

References (54)

  • H. Davies et al.

    Somatic mutations of the protein kinase gene family in human lung cancer

    Cancer Res

    (2005)
  • V. Davalos et al.

    High EPHB2 mutation rate in gastric but not endometrial tumors with microsatellite instability

    Oncogene

    (2007)
  • E.B. Pasquale

    Eph–ephrin promiscuity is now crystal clear

    Nat Neurosci

    (2004)
  • K. Kullander et al.

    Mechanisms and functions of Eph and ephrin signalling

    Nat Rev Mol Cell Biol

    (2002)
  • E.B. Pasquale

    EPH receptor signalling casts a wide net on cell behaviour

    Nat Rev Mol Cell Biol

    (2005)
  • A. Palmer et al.

    Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function

    Genes Dev

    (2003)
  • Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ,...
  • M. van de Wetering et al.

    The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells

    Cell

    (2002)
  • H. Clevers et al.

    EphB/EphrinB receptors and Wnt signaling in colorectal cancer

    Cancer Res

    (2006)
  • A. Gregorieff et al.

    Wnt signaling in the intestinal epithelium: from endoderm to cancer

    Genes Dev

    (2005)
  • E. Batlle et al.

    Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB

    Cell

    (2002)
  • J. Holmberg et al.

    EphB receptors coordinate migration and proliferation in the intestinal stem cell niche

    Cell

    (2006)
  • A.C. Andres et al.

    Eph and ephrin signaling in mammary gland morphogenesis and cancer

    J Mammary Gland Biol

    (2003)
  • N. Munarini et al.

    Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase

    J Cell Sci

    (2002)
  • N. Prevost et al.

    Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets

    Proc Natl Acad Sci U S A

    (2005)
  • H.Y. Luo et al.

    EphB6-null mutation results in compromised T cell function

    J Clin Invest

    (2004)
  • G. Yu et al.

    Ephrin-B1 is critical in T-cell development

    J Biol Chem

    (2006)
  • Cited by (118)

    • Modelling the dynamics of mammalian gut homeostasis

      2023, Seminars in Cell and Developmental Biology
      Citation Excerpt :

      For instance, regions of stem cells, transit-amplifying cells and terminally-differented cells are well-defined spatially. This has been proposed to rely on cell sorting via differential cortical tensions, spatially enforced by gradients of Eph/Ephrin, a classical ligand-receptor pair controlling compartments in a number of biological settings [59]. Furthermore, even within individual compartments, relative cell-cell positions are under tight control: as pointed out above, in the crypts of the small intestine, Lgr5 + stem cells and Paneth cells are intermingled in a salt-and-pepper manner [3].

    • Molecular Patho-mechanisms of cervical cancer (MMP1)

      2022, Annals of Medicine and Surgery
    • EphB4: A promising target for upper aerodigestive malignancies

      2018, Biochimica et Biophysica Acta - Reviews on Cancer
    View all citing articles on Scopus
    View full text