Localization of endoplasmic reticulum (ER) chaperones to the cell surface is an adaptive mechanism for cells to expand the functionality of these proteins in response to stress by activating signaling pathways distinct from their ER functions, thereby impacting cell survival and signaling. In cancer, cell-surface ER chaperones have been reported to regulate oncogenic signaling pathways, proliferation and cell adhesion through interactions with other cell surface proteins. The emerging role of peripheral cell surface GRP78 (csGRP78), traditionally regarded as an ER luminal chaperone, as a multifunctional co-receptor for many different types of cell surface proteins presents novel opportunities for therapeutic interventions. One such cell surface protein is Semaphorin4D (Sema4D). Sema4D was originally discovered as a cell surface cleavable ligand and neuronal axon guidance cue that mobilizes the actin cytoskeleton to facilitate neuronal growth cone homing during development. In cancer, cell surface Sema4D expression is pro-metastatic and pro-angiogenic. Sema4D has been shown to be highly expressed in the breast cancer and epidemiological studies have demonstrated that Sema4D expression in breast cancer patients confers a poor prognosis and high probability of metastatic organotropism. Our recent advances have preliminarily identified a critical role for GRP78 in facilitating Semaphorin4D (Sema4D) trafficking. We show that Sema4D forms a direct protein-protein interaction with GRP78 and that GRP78 may facilitate membrane trafficking of Sema4D to the cell surface, where it exerts pro-angiogenic and metastatic effects. Furthermore, csGRP78 may interact with and facilitate many of the functions of Sema4D. Understanding the conditions by which GRP78 contributes to surface expression of Sema4D and the downstream effects may lead to novel therapeutics that abrogate the effects of Sema4D in cancer and to the elucidation of novel mechanisms by which Sema4D trafficking in cancer is regulated by GRP78.

Citation Format: Anthony Carlos, Yuan-Li Tsai, Yan Ma, Amy Lee. Trafficking of Semaphorin4D is regulated by endoplasmic reticulum chaperone GRP78 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB199.