• An alternative pathway for membrane protein biogenesis at the endoplasmic reticulum

      O’Keefe, Sarah; orcid: 0000-0002-1744-0198; email: sarah.okeefe@manchester.ac.uk; Zong, Guanghui; orcid: 0000-0002-7335-039X; Duah, Kwabena B.; Andrews, Lauren E.; Shi, Wei Q.; orcid: 0000-0001-5453-1753; High, Stephen; orcid: 0000-0002-4532-8152; email: stephen.high@manchester.ac.uk (Nature Publishing Group UK, 2021-07-01)
      Abstract: The heterotrimeric Sec61 complex is a major site for the biogenesis of transmembrane proteins (TMPs), accepting nascent TMP precursors that are targeted to the endoplasmic reticulum (ER) by the signal recognition particle (SRP). Unlike most single-spanning membrane proteins, the integration of type III TMPs is completely resistant to small molecule inhibitors of the Sec61 translocon. Using siRNA-mediated depletion of specific ER components, in combination with the potent Sec61 inhibitor ipomoeassin F (Ipom-F), we show that type III TMPs utilise a distinct pathway for membrane integration at the ER. Hence, following SRP-mediated delivery to the ER, type III TMPs can uniquely access the membrane insertase activity of the ER membrane complex (EMC) via a mechanism that is facilitated by the Sec61 translocon. This alternative EMC-mediated insertion pathway allows type III TMPs to bypass the Ipom-F-mediated blockade of membrane integration that is seen with obligate Sec61 clients.
    • The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

      Xu, Qiuping; Zhang, Jingwei; Telfer, Brian A.; Zhang, Hao; Ali, Nisha; Chen, Fuhui; Risa, Blanca; Pearson, Adam J.; Zhang, Wei; Finegan, Katherine G.; orcid: 0000-0003-2885-0122; et al. (Nature Publishing Group UK, 2021-05-12)
      Abstract: There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.
    • Ultraviolet light-induced collagen degradation inhibits melanoma invasion

      Budden, Timothy; Gaudy-Marqueste, Caroline; Porter, Andrew; orcid: 0000-0002-3353-7002; Kay, Emily; Gurung, Shilpa; Earnshaw, Charles H.; orcid: 0000-0002-7926-8506; Roeck, Katharina; Craig, Sarah; orcid: 0000-0003-1928-582X; Traves, Víctor; Krutmann, Jean; orcid: 0000-0001-8433-1517; et al. (Nature Publishing Group UK, 2021-05-12)
      Abstract: Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.