Ras signaling through RASSF proteins

Abstract

There are six core RASSF family proteins that contain conserved Ras Association domains and may serve as Ras effectors. They lack intrinsic enzymatic activity and appear to function as scaffolding and localization molecules. While initially being associated with pro-apoptotic signaling pathways such as Bax and Hippo, it is now clear that they can also connect Ras to a surprisingly broad range of signaling pathways that control senescence, inflammation, autophagy, DNA repair, ubiquitination and protein acetylation. Moreover, they may be able to impact the activation status of pro-mitogenic Ras effector pathways, such as the Raf pathway. The frequent epigenetic inactivation of RASSF genes in human tumors disconnects Ras from pro-death signaling systems, enhancing Ras driven transformation and metastasis. The best characterized members are RASSF1A and RASSF5 (NORE1A).

MiR-214 regulates oral cancer KB cell apoptosis through targeting RASSF5

“…In addition, activated Ras also plays a critical role in maintaining cell homeostasis by regulating cell aging, differentiation, cycle arrest, and apoptosis (Vos et al, 2003). RASSF5 is a member of the Ras receptor family located on chromosome lq32.1 (Donninger et al, 2016) and contains a Ras association domain and a C-terminal SARAH domain (Salvador, Rassf, Hippo domain). RASSF5, a tumor suppressor gene, was found to be down-regulated in multiple tumor tissues and cell lines in cancers (Hesson et al, 2003;Lee et al, 2010) such as osteosarcoma (Zhou et al, 2014), esophageal cancer , lung cancer (Hesson et al, 2003), liver cancer (Calvisi et al, 2009), and gastric cancer (Han et al, 2015).…”

“…Activated Ras can form a continuous stimulation signal to trigger cell proliferation and inhibit apoptosis for tumor occurrence (Calaf & Abarca-Quinones, 2016). Ras association domain family member 5 (RASSF5), a member of the RASSF family, is the human homologue of the mouse Ras receptor Nore1 (Donninger et al, 2016). RASSF5 can bind to mammalian sterile 20-like kinase 1 (Mst1) through its C-terminal SARAH domain structure, leading to the translocation of Mst1 to the nucleus, phosphorylation of transcriptional factor FOXO3a, and subsequent initiation of cell apoptosis (Praskova et al, 2004).…”

Intracellular and intercellular signaling networks in cancer initiation, development and precision anti-cancer therapy

“…Our short summary and the papers of this special issue [25,29,30,33,36,39,42,52,57] highlight the promises and challenges of using signaling networks (including RAS-related signaling events) in the description of cancer initiation and development, metastasis and the emergence of drug resistance. As key messages we emphasize that…”

“…The approaches outlined above and in the contributions of this special issue [25,29,30,33,36,39,42,52,57] may overcome the current Nietzschean dilemma of cancer cell targeting: “what does not kill me makes me stronger” [60]. …”

“…This analysis suggests, that successful therapeutic interventions must inhibit multiple pathways at the same time [31,32]. As another key example of RAS-centered signaling network cross-talks, Geoffrey Clark and co-workers [33–35] summarize our current knowledge on RASSF family with six core scaffolding RASSF proteins that contain conserved RAS-association domains. Besides the involvement of RASSF members in pro-apoptotic signaling pathways, such as BAX and Hippo, RASSF proteins can also connect RAS to a surprisingly broad range of signaling pathways that control senescence, microtubule dynamics, protein turnover, inflammation, autophagy and DNA repair.…”