Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer

Abstract

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.

Evaluation of NF1 and RASA1 gene expression in endometriosis

“…Several pathways, including PI3K / AKT and MAPK, which play an important role in cell survival and growth, can be interconnected and activated by Ras linked to GTP [14] . RASA1 and NF1 proteins, which are RasGAPs (Ras-GTPase Activating Proteins), terminate the active Ras state by hydrolyzing GTP to GDP, thus negatively regulating the Ras pathway [15] . Accordingly, the development of various mutations and disruption of the expression of this tumor suppressor RasGAPs can lead to the formation of various types of cancers as well as endometriosis [16] , [17] .…”

An update on the tumor-suppressive functions of the RasGAP protein DAB2IP with focus on therapeutic implications

“…DAB2IP mediates tumor suppression ensuring the inhibition of multiple oncogenic pathways, as it has been thoroughly reviewed previously [1,2,10,11]. Recent studies showed that DAB2IP counteracts tumor growth and metastasis also cooperating with other tumor suppressors.…”

“…In multiple solid tumors, DAB2IP is clearly downregulated and its expression levels negatively correlate with tumor growth, angiogenesis, lymph node metastasis, advanced clinical stage, and resistance to therapies, establishing it function as a tumor suppressor [5][6][7][8][9]. Although its relevance in tumor initiation remains undefined, available evidences strongly indicate that loss of DAB2IP represents an advantage for cancer progression and metastasis [1,2,10,11]. Notably, its mutation rate in cancers is relatively limited, and its loss-of-function is most frequently dependent on transcriptional silencing or post-transcriptional inactivation mechanisms; this makes DAB2IP a strong candidate for the development of therapeutics aimed to restore its tumorsuppressive function.…”

Induced Coma, Death, and Organ Transplantation: A Physiologic, Genetic, and Theological Perspective

“…Thus, CDC42 stimulates mTORC1 activity and thereby upregulates tissue-specific transcription factors that are essential for neural progenitor formation. Further, by promoting EGFR degradation, it was found that CDC42b and ACK stimulate autophagy and trigger neural progenitor cells to differentiate into neurons [ 48 ].…”