TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes

Transforming Growth Factor beta 1 (TGF beta 1) is a critical regulator of tumor progression in response to HRas. Recently, TGF beta 1 has been shown to trigger ER stress in many disease models; however, its role in oncogene-induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol-requiring enzyme 1 alpha (IRE1 alpha) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1 alpha and (PKR)-like endoplasmic reticulum kinase (PERK) to mediate the tumor-suppressive roles of TGF beta 1 in mouse keratinocytes expressing mutant forms of HRas. TGF beta 1 suppressed IRE1 alpha phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously activating the PERK pathway. However, the increase in ER stress indicated an uncoupling of ER stress and IRE1 alpha activation by TGF beta 1. Pharmacological and genetic approaches demonstrated that TGF beta 1-dependent dephosphorylation of IRE1 alpha was mediated by PERK through RNA Polymerase II Associated Protein 2 (RPAP2), a PERK-dependent IRE1 alpha phosphatase. In addition, TGF beta 1-mediated growth arrest in oncogenic HRas keratinocytes was partially dependent on PERK-induced IRE1 alpha dephosphorylation and inactivation. Together, these results demonstrate a critical cross-talk between UPR proteins that is important for TGF beta 1-mediated tumor suppressive responses.

Automated summary

The study found that TGF beta 1 plays a critical role in regulating tumor progression and can induce ER stress. The results showed that TGF beta 1 suppresses the phosphorylation and activation of IRE1 alpha through activating the PERK pathway, thereby exerting tumor-suppressive effects. In addition, TGF beta 1 also partially depends on the PERK-induced IRE1 alpha dephosphorylation and inactivation through PERK-dependent IRE1 alpha phosphatase.