br Concluding remarks br Transparency document br
Acknowledgements Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572 (RS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Introduction Kinases present one of the largest JNJ26481585 of enzymes. Protein kinases regulate key biological processes including cell differentiation, proliferation, and motility . Receptor tyrosine kinases (RTKs) are transmembrane proteins that undergo a conformational change upon the binding of signaling molecules to the extracellular (N-terminal) domain. The conformational change triggers autophosphorylation of tyrosine residues in the intracellular domain of the RTK. Subsequently, the activated RTKs can phosphorylate a variety of cytoplasmic signaling proteins, which transduce a cellular response. Among other processed, this signaling may induce the transcription of specific genes . The Eph receptors family in erythropoietin-producing hepatocellular carcinoma belongs to the largest class of RTKs. Like other RTKs, they transduce signals from the cell exterior to the cell interior via the ligand-induced activation of their kinase domains. Eph receptor tyrosine kinases constitute a large family of transmembrane proteins, containing a single cytoplasmic kinase domain that is activated in response to the binding of ephrin ligands to the extracellular globular domain of the receptor . Eph receptors, however, have distinctive features: instead of binding soluble ligands, they generally mediate contact-dependent cell-cell communication by interacting with surface-associated ligands (ephrins on neighboring cells). Ephrins can also attenuate signaling through Eph receptors that are co-expressed on the same cell. . Based on their ligand-binding characteristics, Ephs have been subdivided into Eph A and Eph B receptors, although there is significant redundancy and cross talk between subclasses . In general, EphA receptors (EphA1-A10) are promiscuously activated by ephrinA ligands (ephrinA1-ephrinA6), whereas EphB receptors (EphB1-EphB6) are activated by ephrinB ligands (ephrinB1-ephrinB3). Cross interactions have been observed between EphB2 and ephrinA5 as well as between EphA4 and ephrinB2/B3. Unlike other receptors in the family, EphB4 display a distinct specificity for its ligand ephrinB2, while exhibiting a very weak binding affinity for either ephrinB1 or ephrinB3 . The EphB4-ephrinB2 interaction plays a prominent role in cardiovascular development and regulates vascularization in malignant tumors . The Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues offer opportunities for Eph/ephrin-targeted drug delivery . In fact, EphB4 overexpression has been linked to several tumor types such as breast, prostate, colon, uterus, melanoma, and ovarian cancer among others , , , , , . Tyrosine kinase EphB4 has been associated with angiogenesis, tumor growth and metastasis, making it a valuable and attractive target for drug design for therapeutic applications. However, the role of EphB4 in cancer remains a matter for debate, since Eph-ephrin interactions have been shown to either promote or inhibit tumor growth . The primary focus of this review is to analyze the structure and function of EphB4, briefly discuss its potential as a target for anticancer therapy and summarize updated research about inhibitors of EphB4 kinase activity.
The structure of the EphB4 protein
The rgulatiory function of EphB4 in cancer The functions of the Eph/ephrin system in cancer are complex because many tumor cells express varying degrees of Eph receptors and ligands. Eph signaling controls cell morphology, adhesion, migration, invasion, and the epithelial phenotype by modifying the organization of the actin cytoskeleton and influencing the activities of integrins and intercellular adhesion molecules , . Eph-ephrin complexes transduce emanate bidirectional signals: forward signals depend on Eph kinase activity for propagation in receptor-expressing cells, whereas reverse signals depend on Src family kinases for propagation in the ephrin-expressing cells . Eph receptors and ephrins are widely expressed in cancer cells and tumor stroma, but may be down regulated in advanced stages of cancer . Moreover, dysregulating mutations affecting Eph function also play a role in cancer pathogenesis . However, although bidirectional signaling promotes tumor angiogenesis, the mechanism underlying its role in cancer progression is poorly understood.