STRUCTURE FUNCTION STUDY OF A NOVEL TUMOR SUPPRESSOR, EPHA

Rockefeller University, New York NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In an array CGH study on ~150 follicular lymphomas we found recurrent deletions affecting Chr. 6q21-25 in ~20-25% of cases and increasing with tumor grade. Using a short hairpin RNA (shRNA) library screen we identify EphA as a novel tumor suppressor gene targeted by this deletion. EphA behaves as a classical tumor suppressor and the remaining allele is subject to extensive methylation. Moreover, knockdown of EphA accelerates tumor development in a mouse model of follicular lymphoma. Strikingly, in normal lymphocytes we find expression of truncated and secreted form of EphA, which acts inhibit oncogenic signaling pathways in lymphocytes. Together, these findings point to EphA as a soluble secreted tumor suppressor protein involved in lymphomagenesis and progression. We now propose to a) examine the effects of EphA loss and exogenous reconstitution in murine lymphoma models, b) study the structures of soluble and full length EphA receptors, and c) use mass spectrometry to delineate the signaling consequences of this novel tumor suppressor pathway. We expect our study will provide new insight into the novel EphA tumor suppressor. Notably, this pathway is triggered by a secreted form of EphA, which indicates that administration of exogenous EphA (or analogues) could re-activate this pathway and produce therapeutic effects in tumors.