Abstract The PLSCR family has been proposed to play a role in the redistribution of plasma membrane phospholipids. Recent work on the PLSCRs has revealed their additional functions such as signal transduction and lipid metabolism. The most studied member of this family, PLSCR1, has been shown to partition into lipid rafts implicating it in the regulation and endocytic trafficking of receptor-signaling complexes, e.g. EGFR. Additionally, PLSCR1 has been implicated in tumorigenesis although the exact mechanism of PLSCR1 is still controversial. In a previous study, we identified PLSCRs, as novel Cripto-1 (CR-1) binding proteins that might modulate CR-1-dependent signaling pathways. In this study, we confirmed that PLSCR1 and PLSCR3 bind to Cripto-1 but also that PLSCR1 also inhibits TGFβ signaling via binding to the receptor complexes for the TGFβ superfamily. We also showed that PLSCR1 mediates protein degradation of type I receptors: Alk4 and TGFβRI but not ActRBII, TGFBRII or BMPRb. Additionally, we demonstrated that PLSCR1 is overexpressed in human breast cancer tissue and in human breast cancer cell lines especially in triple-negative MDA-MB-231 and MDA-MB-468. We also showed that knockout of PLSCR1 inhibits migration, invasion and anchorage independent growth of MDA-MB-231, and that TGFβ influences PLSCR1 cellular distribution in those cells. Citation Format: Margaret Klauzinska, Hideaki Karasawa, Maria Cristina Rangel, Nadia Castro, Alyson Baker, Daniel Bertolette, Julie Krask, David Salomon. PLSCR1- a modifier of TGFβ signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2226. doi:10.1158/1538-7445.AM2015-2226