Akt-mediated Ephexin1–Ras interaction promotes oncogenic Ras signaling and colorectal and lung cancer cell proliferation
| Autor: | Sung-Chul Lim, Joohyun Ryu, In-Youb Chang, Jeeho Kim, Ho Jin You, Jung-Hee Lee, Young Jin Jeon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Cancer Research Lung Neoplasms MAP Kinase Signaling System Immunology Mice Nude GTPase Biology medicine.disease_cause Models Biological Article Cellular and Molecular Neuroscience Phosphoserine Targeted therapies Protein Domains Cell Line Tumor medicine Animals Guanine Nucleotide Exchange Factors Humans Amino Acid Sequence RNA Messenger Phosphorylation Cancer models Cell Proliferation Mice Inbred BALB C QH573-671 Kinase Erythropoietin-producing hepatocellular (Eph) receptor Cell Biology Oncogenes Prognosis Up-Regulation Gene Expression Regulation Neoplastic HEK293 Cells Fibroblast growth factor receptor Cancer cell Cancer research ras Proteins Guanine nucleotide exchange factor Signal transduction Carcinogenesis Colorectal Neoplasms Cytology Proto-Oncogene Proteins c-akt Protein Binding |
| Zdroj: | Cell Death and Disease, Vol 12, Iss 11, Pp 1-14 (2021) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | Oncogenic Ras mutations are frequently observed in solid tumor cells and are present in pancreatic cancer, colorectal cancer (CRC), and lung cancer (LC) [1, 2]. Mutational activation of K-Ras in these tissues is sufficient to initiate neoplasia in mice [3–5]. Thus, understanding the mechanisms behind Ras-induced oncogenesis is an important goal in cancer therapy. A significant consequence of Ras-mediated signal transduction is the altered expression of a large number of genes. It is well established that canonical Ras signaling is coupled to transcriptional regulation through the activation of the MAPK cascade, which involves the sequential phosphorylation and activation of the serine/threonine kinases RAF, MEK1/2, and ERK1/2 [6–12]. More recently, new regulatory factors that directly interact with K-Ras were identified and shown to play a crucial role in the full range of K-Ras oncogenic phenotypes [13–19]. Despite decades of effort, many aspects of the molecular mechanism underlying Ras-induced tumorigenesis and possible therapeutic targeting remain difficult to identify. Ephexin1 is a member of the DbI family of guanine nucleotide exchange factors (GEFs) and serves as a direct link between Eph receptors and the Rho-family of GTPases [20, 21]. Ephexin1 is highly expressed in the nervous system during development and is involved in many neurophysiological events [22–26]. It is phosphorylated by the Src family of kinases and by fibroblast growth factor receptor signaling, leading to the regulation of GEF activity, which in turn regulates actin cytoskeletal dynamics [22, 27]. Through extensive analysis of the gene expression patterns in cells with activated forms of Ras and Rho families, it was found that Ephexin1 was highly upregulated by H-RasG12V in NIH3T3 cells [28]. In humans, Ephexin1 is upregulated in papillary thyroid cancers (PTC) and has been identified as the most reliable marker for PTC diagnosis [29]. Therefore, the implication of these results is that Ephexin1 may be involved in tumor proliferation and progression, particularly in cancer cells with oncogenic Ras mutations. However, the functional consequences of Ephexin1 had not yet been addressed. In the present study, we show that Ephexin1 is overexpressed in both CRC and LC tissues and is associated with a poor prognosis for both cancers, and provide evidence for the functional and clinical significance of Ephexin1 and identify a potential therapeutic target for the case of CRC and LC caused by Ras mutations. |
| Databáze: | OpenAIRE |
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