Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer
Abstract
Simple Summary
Abstract
1. Introduction
2. The Brakes: GAPs as Negative Regulators of Ras Activity
- RASA1 (Ras p21 protein activator 1)/p120GAP was the first RasGAP to be identified. In early studies, RASA1 appeared to be essential for embryonic blood vessel development [13]; subsequently, a germline mutation in RASA1 was associated with vascular malformations [14]. Although RASA1 can mitigate Ras activity, its role in cancer has remained unclear for a long time; recent works described RASA1 inhibition by non-coding RNA in multiple aggressive tumors, supportive of a tumor-suppressive activity [15,16,17,18,19].
- Neurofibromin (NF1) is perhaps the most extensively studied RasGAP. Germline mutations of NF1 are associated with the familiar disorder Neurofibromatosis Type 1. Germline NF1 mutations cause tumors along the nervous system, including neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). NF1 patients are also predisposed to develop gliomas, melanoma, and myeloid leukemia [20]. NF1 is also somatically altered in multiple sporadic tumors, including skin, lung, breast, and ovarian cancers [21], where its tumor-suppressive function seems to be linked primarily to Ras inhibition [11].
- The GAP1 family includes RASA2 (Ras p21 protein activator 2)/GAP1m, RASA3 (Ras p21 protein activator 3)/GAPIP4BP, RASA4 (Ras p21 protein activator 4)/CAPRI, and RASAL1 (Ras protein activator like 1). Members of this group share large significant sequence homology and act as dual GAPs, binding and inactivating Ras and Rap1 GTPases. All members of this group are clearly implicated in cancer. For example, the recurrent inactivation of RASA2 in melanoma favors constitutive activation of Ras signaling [22], and the frequent downregulation of RASA4 in myelomonocytic leukemia correlates with poor prognosis and higher risk of relapse after therapy [23]. Furthermore, the recurrent deletion of chromosome 13, which includes the RASA3 gene, in Burkitt and T-cell lymphomas and in acute myeloid leukemia (AML) suggests a potential role of RASA3 in these blood tumors [24]. Finally, RASAL1 displays MAPK- and PI3K-suppressing activities in multiple tumors, including thyroid cancer [25,26].
- The SynGAP family includes SynGAP (synaptic Ras GTPase-Activating Protein 1), DAB2IP (Dab2 interacting protein), RASAL2 (Ras protein activator like 2), and RASAL3 (Ras protein activator like 3). The founding member SynGAP is expressed only in neuronal tissue; germline SynGAP mutations have been associated with intellectual disabilities and autism [27]. RASAL2 functions as a tumor suppressor in a broad range of human tumors, including lung, ovarian, breast, and bladder cancer; low RASAL2 expression often correlates with aberrant Ras-ERK activation and worst prognosis [28,29]. Curiously, RASAL2 has also been described as an oncogene, based on its ability to promote EMT and metastasis in several tumors, fostering YAP (Yes1 associated transcriptional regulator), Wnt/β-catenin, PI3K/Akt, and Rac1 signaling [28]. DAB2IP is a tumor suppressor whose expression and function are altered in multiple human malignancies, causing uncontrolled activation of multiple oncogenic pathways, including Ras, NF-κB, PI3K/Akt, and Wnt/β-catenin [30,31]. Much less studied, RASAL3 epigenetic silencing in fibroblasts was linked to reprogramming of the tumor stroma in prostate cancer patients failing androgen deprivation therapy [32].
- The IQGAPs (IQ motif containing GTPase-Activating Protein) are cytoskeletal scaffold proteins with high sequence homology but variable tissue distribution. Despite the presence of a GAP domain, the IQGAPs are not Ras inhibitors, since the GAP domain lacks an arginine essential to assist Ras in GTP hydrolysis [11]. For this reason, they will not be considered here.
- Plexins are transmembrane receptors that bind semaphorins and regulate cell migration and angiogenesis. Plexins display GAP activity to Ras and Rap (a sub-family of Ras homologs) so they have a dual specificity [33]. Plexins also bind and modulate cytosolic tyrosine kinases, serine/threonine kinases, and other adaptors and scaffolding proteins, orchestrating complex signaling networks. Functional alterations in plexins cause cardiovascular and neuronal disorders, but their role in cancer is unclear: loss of plexins, specially plexin B1, was correlated with aggressive tumors [34]. However, there is also evidence of an oncogenic role for plexins in multiple malignancies [35,36,37]. Given their role as receptors and their complex Ras-independent functions, plexins will not be considered in this review.
3. Mutation of RasGAPs in Cancer
4. Transcriptional Repression of RasGAPs in Cancer
5. Post-Transcriptional Inhibition of RasGAPs in Cancer
6. Post-Translational Inhibition of RasGAPs in Cancer
6.1. Phosphorylation
6.2. Protein–Protein Interactions
6.3. Subcellular Localization
6.4. Protein Degradation
7. Control of RasGAPs Levels and Functions by Extracellular Inputs
8. Conclusions
Funding
Acknowledgments
Conflicts of Interest
References
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Gene | Tumor | References |
---|---|---|
NF1 | Hepatocellular carcinoma | [9] |
RASA4 | Myelomonocytic leukemia | [23] |
RASAL1 | Hepatocellular and nasopharyngeal carcinoma; breast, thyroid, and bladder cancer; NK/T-cell lymphoma | [9,25,26,63,68], reviewed in [69] |
RASAL2 | Renal carcinoma, breast cancer | [60,70] |
RASAL3 | Prostate CAFs | [32] |
DAB2IP | Hepatocellular carcinoma; lung, breast, prostate, and gastrointestinal cancer; ovarian carcinoma | [9,67], reviewed in [30] |
(a) number of cancer-related miRNAs predicted to bind a single RasGAP | ||
RasGAP | TargetScan conserved sites | DIANA microT-CDS |
RASA1 | 42 (53) | 111 (350) |
NF1 | 33 (42) | 150 (388) |
RASA2 | 51 (57) | 102 (288) |
RASA3 | 0 (0) | 15 (39) |
RASA4 | 0 (0) | 24 (121) |
RASAL1 | 11 (11) | 13 (34) |
RASAL2 | 57 (79) | 91 (354) |
RASAL3 | 0 (0) | 15 (58) |
SYNGAP1 | 24 (34) | 56 (257) |
DAB2IP | 31 (41) | 41 (132) |
(b) cancer-related miRNAs predicted to bind at least four RasGAPs | ||
Targeted RasGAPs | onco-miRNAs | |
NF1, RASA1, RASA2, RASA3, RASAL1, RASAL2, SYNGAP1 | hsa-miR-3163 | |
DAB2IP, NF1, RASA1, RASA2, RASA3, RASAL2 | hsa-miR-548c-3p | |
DAB2IP, NF1, RASA1, RASA2, RASAL1, RASAL2 | hsa-miR-5692a | |
NF1, RASA1, RASA2, RASA4, RASAL2 | hsa-miR-5590-3p | |
DAB2IP, NF1, RASA1, RASA2, RASAL2 | hsa-miR-582-5p | |
DAB2IP, NF1, RASA2, RASA3, RASAL2 | hsa-miR-27b-3p, hsa-miR-27a-3p | |
NF1, RASA2, RASAL1, RASAL2, SYNGAP1 | hsa-miR-4282 | |
NF1, RASA1, RASA2, RASA4 | hsa-miR-129-5p | |
NF1, RASA1, RASA2, RASAL2 | hsa-miR-30d-5p, hsa-miR-30b-5p, hsa-miR-320c, hsa-miR-4429, hsa-miR-30a-5p, hsa-miR-30e-5p, hsa-miR-320b, hsa-miR-495-3p, hsa-miR-33a-3p, hsa-miR-320d | |
NF1, RASA1, RASA2, SYNGAP1 | hsa-miR-224-3p | |
DAB2IP, NF1, RASA,1, RASA3 | hsa-miR-588 | |
NF1, RASA2, RASA3, RASAL2 | hsa-miR-543 | |
NF1, RASA2, RASA4, RASAL2 | hsa-miR-4775 | |
DAB2IP, NF1, RASA2, RASAL2 | hsa-miR-126-5p | |
DAB2IP, NF1, RASA2, SYNGAP1 | hsa-miR-130a-5p | |
DAB2IP, RASA4, RASAL1, RASAL3 | hsa-miR-1285-3p | |
RASA4, RASAL2, RASAL3, SYNGAP1 | hsa-miR-1275 |
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Bellazzo, A.; Collavin, L. Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer. Cancers 2020, 12, 3066. https://doi.org/10.3390/cancers12103066
Bellazzo A, Collavin L. Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer. Cancers. 2020; 12(10):3066. https://doi.org/10.3390/cancers12103066
Chicago/Turabian StyleBellazzo, Arianna, and Licio Collavin. 2020. "Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer" Cancers 12, no. 10: 3066. https://doi.org/10.3390/cancers12103066
APA StyleBellazzo, A., & Collavin, L. (2020). Cutting the Brakes on Ras—Cytoplasmic GAPs as Targets of Inactivation in Cancer. Cancers, 12(10), 3066. https://doi.org/10.3390/cancers12103066