Endoplasmic reticulum stress activates SRC, relocating chaperones to the cell surface where GRP78/CD109 blocks TGF-β signaling

• DOI: 10.1073/pnas.1714866115
• Publication Date: 2018-04-13T19:25:22Z
• Authors: Yuan-Li Tsai; Dat P. Ha; He Zhao; Anthony J. Carlos; Shan Wei; Tsam Kiu Pun; Kaijin Wu; Ebrahim Zandi; Kevin Kelly; Amy S. Lee
• Keywords: 0301 basic medicine; Smad2 Protein; Endoplasmic Reticulum Stress; GPI-Linked Proteins; Neoplasm Proteins; Enzyme Activation; Protein Transport; 03 medical and health sciences; HEK293 Cells; src-Family Kinases; Antigens, CD; Transforming Growth Factor beta; MCF-7 Cells; Humans; ADP-Ribosylation Factor 1; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Adaptor Proteins, Signal Transducing; HeLa Cells; Signal Transduction

Significance Endoplasmic reticulum (ER) stress-mediated relocalization of ER chaperones to the cell surface allows cells to expand their functionality beyond the ER, impacting survival, death, migration, and immunity. However, little is known about the underlying mechanisms and the interacting partners on the cell surface. Both protooncogene tyrosine-protein kinase SRC and TGF-β are important players in cell signaling, growth, apoptosis, and survival. Our discoveries that SRC activation is the driving force in the escape of ER luminal proteins to the cell surface via disruption of retrograde transport provide an oncogenic function for SRC and uncover a mechanism for regulation of TGF-β signaling via the GRP78/CD109 partnership, with therapeutic implications in cancer and other human diseases.