Abstract
Simple SummaryGTPase-Activating Proteins (RasGAPs) are a group of structurally related proteins with a fundamental role in controlling the activity of Ras in normal and cancer cells. In particular, loss of function of RasGAPs may contribute to aberrant Ras activation in cancer. Here we review the multiple molecular mechanisms and factors that are involved in downregulating RasGAPs expression and functions in cancer. Additionally, we discuss how extracellular stimuli from the tumor microenvironment can control RasGAPs expression and activity in cancer cells and stromal cells, indirectly affecting Ras activation, with implications for cancer development and progression.The Ras pathway is frequently deregulated in cancer, actively contributing to tumor development and progression. Oncogenic activation of the Ras pathway is commonly due to point mutation of one of the three Ras genes, which occurs in almost one third of human cancers. In the absence of Ras mutation, the pathway is frequently activated by alternative means, including the loss of function of Ras inhibitors. Among Ras inhibitors, the GTPase-Activating Proteins (RasGAPs) are major players, given their ability to modulate multiple cancer-related pathways. In fact, most RasGAPs also have a multi-domain structure that allows them to act as scaffold or adaptor proteins, affecting additional oncogenic cascades. In cancer cells, various mechanisms can cause the loss of function of Ras inhibitors; here, we review the available evidence of RasGAP inactivation in cancer, with a specific focus on the mechanisms. We also consider extracellular inputs that can affect RasGAP levels and functions, implicating that specific conditions in the tumor microenvironment can foster or counteract Ras signaling through negative or positive modulation of RasGAPs. A better understanding of these conditions might have relevant clinical repercussions, since treatments to restore or enhance the function of RasGAPs in cancer would help circumvent the intrinsic difficulty of directly targeting the Ras protein.
Highlights
Ras proteins (K-Ras, N-Ras, and H-Ras) are small monomeric GTPases that modulate cell fate by linking receptor activation to intracellular signaling, thereby controlling cell growth, survival, migration, and metabolism [1].Ras signaling can be initiated by receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs), and integrin family members
Various mechanisms can cause the loss of function of Ras inhibitors; here, we review the available evidence of RasGAP inactivation in cancer, with a specific focus on the mechanisms
A recent report showed that EZH2-dependent DAB2IP repression induces a stem-like phenotype in ovarian cancer cells by unleashing WNT5B-dependent planar cell polarity signaling; this study provides proof of concept that pharmacologic inhibition of EZH2 can restore DAB2IP expression and reduce stem features and aggressiveness of ovarian cancer cells [67]
Summary
Ras proteins (K-Ras, N-Ras, and H-Ras) are small monomeric GTPases that modulate cell fate by linking receptor activation to intracellular signaling, thereby controlling cell growth, survival, migration, and metabolism [1]. In a large-scale analysis of the patterns of somatic alterations in Rasout activation a complex oncogenic circuit that promotes cancer, the RTK-Ras axis turned to be theestablishes canonical pathway with the highest median frequency tumor initiation, growth, and dissemination, to such an extent that some authors have proposed the of mutation [3]. In tumors mutation, cancer, the RTK-Ras axis turned out to be the canonical pathway with the highest median frequency multiple events can phenocopy Ras hyperactivation [6]. GTPases, Ras activity is controlled by activators andisinhibitors; the cancer and myeloma, tumors that have a lower mutation rate compared to other cancers absence of RAS gene alterations, one important mechanism of Ras hyperactivation in cancer is the most GTPases, Ras activityHere, is controlled by activators andclass inhibitors; in the the GTPaseabsence loss Like of function of Ras inhibitors.
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