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The coordinated movement of cells and cell layers is an essential process involved in shaping the vertebrate body during normal development, while aberrant cell migration and adhesion in adult organisms are hallmarks of metastatic cancer progression. Eph-like receptors and their ligands, called ‘ephrins’, are essential in facilitating and directing the movement of cells and cell layers during various developmental processes. Whilst scarcely expressed in adult tissues except the CNS, Eph and ephrin expression is elevated in highly invasive breast, lung, colon and brain tumours, lymphoblastoid leukemia and in malignant melanoma. Our laboratory seeks to elucidate the molecular mechanism that is used by Eph receptors to affect cell adhesion and migration during embryogenesis and oncogenesis, and to use this knowledge for the development of potential anti-cancer drugs. We found that adherent EphA3 bearing cells respond to receptor activation with rapid cell rounding and detachment (see attached movies), while kinase-inactive EphA receptors can act as adhesion molecules for ephrin expressing cells and may contribute to the preferred involvement of the CNS in metastatic melanoma. Furthermore, as increased Eph receptor expression levels correlate with metastatic melanoma progression, we are evaluating an anti-EphA3 monoclonal antibody as a potential anti-cancer reagent.

Retraction of cell processes and cell rounding of malignant melanoma cells after EphA3 stimulation. You can download a movie of this process in .mov format (1.7 Mb) or .avi format (7.5 Mb) or view an animated GIF image file (0.96 Mb).

Lab members involved in the research:

• Martin Lackmann
• Sabine Kleikamp
• Maureen Nerrie

Publications:
The role of the Eph-ephrin signalling system in the regulation of developmental patterning.
Coulthard MG, Duffy S, Down M, Evans B, Power M, Smith F, Stylianou C, Kleikamp S, Oates A, Lackmann M, Burns GF, Boyd AW.
Int J Dev Biol. 46: 375-384 (2002). [Medline entry]

Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling.
Lawrenson ID, Wimmer-Kleikamp SH, Lock P, Schoenwaelder SM, Down M, Boyd AW, Alewood PF, Lackmann M.
J Cell Sci. 115: 1059-1072 (2002). [Medline entry]

Signals from Eph and Ephrin Proteins: A Developmental Toolkit.
Boyd AW, Lackmann M.
Dec 11(112):RE20 (2001). [Medline entry]

Signals from Eph and Ephrin Proteins: A Developmental Toolkit.
Boyd AW, Lackmann M.
Science STKE, accepted for publication (2001).

Ephrin-A5 induced rounding and de-adhesion of EphA3 expressing 293T and melanoma cells involves Crk-mediated signaling.
Lawrenson ID, Kleikamp SH, Lock P, Schoenwaelder SM, Down M, Boyd AW, Alewood PF, Lackmann M.
J. Cell. Sci., accepted for publication.

Himanen J-P, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M and Nikolov DB
Crystal structure of an Eph receptor-Ephrin Complex.
Nature 414: 933-938 (2001).

An early developmental role for eph-ephrin interaction during vertebrate gastrulation.
Oates AC, Lackmann M, Power MA, Brennan C, Down LM, Do C, Evans B, Holder N, Boyd AW.
Mech Dev. 83:77-94 (1999). [Medline entry]

Distinct subdomains of the EphA3 receptor mediate ligand binding and receptor dimerization.
Lackmann M, Oates AC, Dottori M, Smith FM, Do C, Power M, Kravets L, Boyd AW.
J Biol Chem. 273:20228-20237 (1998). [Medline entry]

Ligand for EPH-related kinase (LERK) 7 is the preferred high affinity ligand for the HEK receptor.
Lackmann M, Mann RJ, Kravets L, Smith FM, Bucci TA, Maxwell KF, Howlett GJ, Olsson JE, Vanden Bos T, Cerretti DP, Boyd AW.
J Biol Chem. 1997 Jun 27;272(26):16521-30. [Medline entry]

Purification of a ligand for the EPH-like receptor HEK using a biosensor-based affinity detection approach.
Lackmann M, Bucci T, Mann RJ, Kravets LA, Viney E, Smith F, Moritz RL, Carter W, Simpson RJ, Nicola NA, Mackwell K, Nice EC, Wilks AF, Boyd AW.
Proc Natl Acad Sci U S A. 93:2523-2527 (1996). [Medline entry]