Abstract Receptor Expressed in Lymphoid Tissues (RELT), is a human TNFR superfamily member (TNFRSF19L) expressed most prominently in the hematopoietic system. Previous reports using RELT knockout mice indicate that RELT functions in part by inhibiting the proliferation and activation of T lymphocytes. RELT is an orphan receptor that has two homologous binding partners, RELL1 and RELL2, and collectively, these three proteins are referred to as RELT family members. This study sought to identify novel protein interactions with RELT family members and to compare the expression of RELT in normal and diseased human tissues. A yeast two-hybrid screen utilizing RELL1 as bait identified the cytoskeletal protein Filamin A (FLNA) as a prospective binding partner and physical interaction between FLNA and RELT family members was confirmed by in vitro co-immunoprecipitation. A truncated mutant of FLNA disrupts the ability of RELT family members to activate the p38 pathway and blocks the ability of RELT to induce death in human epithelial cells. Western blotting revealed endogenous RELT family members are most significantly upregulated in the breast cancer cell lines MDA-MB-231 and MCF-7, as well as the lung cancer cell line H358. Preliminary immunohistochemistry results reveal a higher intensity of RELT staining in both breast cancer and lung cancer human biopsies versus non-malignant tissue. Additionally, overexpression of RELT family members enhanced apoptosis in MDA-MB-231 and H358 cells as measured by X-gal morphology and luciferase assays. Collectively, these results further our understanding of signal transduction pathways associated with RELT family members and report the novel finding that RELT is upregulated in human breast and lung cancers. Supported by California Northstate University, College of Medicine, Seed Grant.