The Unfolded Protein Response Sensor PERK Mediates Mechanical Stress-induced Maturation of Focal Adhesion Complexes in Glioblastoma Cells

Abstract

AbstractStiffening of the brain extracellular matrix (ECM) in glioblastoma leads to mechanical stress, which is known to contribute to tumor formation and progression. Previously, we found that protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), a component of the unfolded protein response (UPR), plays a role in the adaptation of glioblastoma stem cells (GSCs) to matrix stiffness through PERK/FLNA dependent F-Actin remodeling. Here, we found that increases in matrix stiffness induces differentiation of GSCs that was not seen in PERK deficient GSCs. Furthermore, we investigated whether PERK is involved in detecting changes in matrix stiffness through focal adhesion complex (FAC) formation and maturation, which are instrumental for transmitting ECM dependent signaling. In PERK deficient GSCs, Vinculin and Tensin expression was decreased, while Talin and Integrin-β1 expression was kept at the same level compared to PERK proficient cells. In addition, in the absence of PERK, Tubulin expression is sharply increased coupled with low Vimentin expression, which was observed as an opposite trend in the presence of PERK. In conclusion, our study reveals a novel role for PERK in regulating the formation of FACs during matrix stiffening, possibly associated with its regulatory capacity in F-Actin remodeling.