Feedback activation of neurofibromin terminates growth factor-induced Ras activation

Hennig, Anne K.; Markwart, Robby; Wolff, Katharina; Schubert, Katja; Cui, Yan; Prior, Ian A.; Esparza-Franco, Manuel A.; Ladds, Graham; Rubio, Ignacio

doi:10.1186/s12964-016-0128-z

Cited by 33 publications

(35 citation statements)

References 65 publications

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“…Among the Ras-GEF families identified in mammals, the Sos proteins are the most widely expressed and functionally relevant for Ras activation by upstream cellular signals. 34,35 According to in silico prediction tools in Tar-getScan, Sos1 has an miR-143 binding site in its 3 0 UTR. To validate Sos1 as a target gene of miR-143, we performed a luciferase AKAO ET AL.…”

Section: Syn-mir-143 Silenced Sos1 By Rnaimentioning

confidence: 99%

Impairment of K‐Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR‐143

et al. 2018

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Despite considerable research on K‐Ras inhibitors, none had been established until now. We synthesized nuclease‐resistant synthetic miR‐143 (miR‐143#12), which strongly silenced K‐Ras, its effector signal molecules AKT and ERK, and the K‐Ras activator Sos1. We examined the anti‐proliferative effect of miR‐143#12 and the mechanism in human colon cancer DLD‐1 cell (G13D) and other cell types harboring K‐Ras mutations. Cell growth was markedly suppressed in a concentration‐dependent manner by miR‐143#12 (IC50: 1.32 nmol L−1) with a decrease in the K‐Ras mRNA level. Interestingly, this mRNA level was also downregulated by either a PI3K/AKT or MEK inhibitor, which indicates a positive circuit of K‐Ras mRNA expression. MiR‐143#12 silenced cytoplasmic K‐Ras mRNA expression and impaired the positive circuit by directly targeting AKT and ERK mRNA. Combination treatment with miR‐143#12 and a low‐dose EGFR inhibitor induced a synergistic inhibition of growth with a marked inactivation of both PI3K/AKT and MAPK/ERK signaling pathways. However, silencing K‐Ras by siR‐KRas instead of miR‐143#12 did not induce this synergism through the combined treatment with the EGFR inhibitor. Thus, miR‐143#12 perturbed the K‐Ras expression system and K‐Ras activation by silencing Sos1 and, resultantly, restored the efficacy of the EGFR inhibitors. The in vivo results also supported those of the in vitro experiments. The extremely potent miR‐143#12 enabled us to understand K‐Ras signaling networks and shut them down by combination treatment with this miRNA and EGFR inhibitor in K‐Ras‐driven colon cancer cell lines.

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Section: Syn-mir-143 Silenced Sos1 By Rnaimentioning

confidence: 99%

Impairment of K‐Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR‐143

et al. 2018

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“…Direct inhibition of mutant KRAS largely remains a pharmacologic challenge and inhibiting the downstream mitogen-activated protein kinase (MAPK) signaling pathway with MEK inhibitors (MEKi) had limited clinical efficacy in KRASmutant tumors (2)(3)(4). One possible explanation is reactivation of the MAPK pathway due to the alleviation of the negative feedback modulation (5,6), which is commonly observed in KRAS-mutant cells (7)(8)(9). In such a scenario, prevention of pathway reactivation would maintain pathway suppression thereby improving antitumor efficacy.…”

Section: Introductionmentioning

confidence: 99%

SHP2 Inhibition Overcomes RTK-Mediated Pathway Reactivation in KRAS-Mutant Tumors Treated with MEK Inhibitors

Lu¹,

Liu²,

Velazquez³

et al. 2019

Molecular Cancer Therapeutics

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FGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with the MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTK) are also feedback-activated in this context. Herein, we profile a large panel of KRAS-mutant cancer cell lines for the contribution of RTKs to the feedback activation of phospho-MEK following MEK inhibition, using an SHP2 inhibitor (SHP099) that blocks RAS activation mediated by multiple RTKs. We find that RTK-driven feedback activation widely exists in KRAS-mutant cancer cells, to a less extent in those harboring the G13D variant, and involves several RTKs, including EGFR, FGFR, and MET. We further demonstrate that this pathway feedback activation is mediated through mutant KRAS, at least for the G12C, G12D, and G12V variants, and wild-type KRAS can also contribute significantly to the feedback activation. Finally, SHP099 and MEK inhibitors exhibit combination benefits inhibiting KRAS-mutant cancer cell proliferation in vitro and in vivo. These findings provide a rationale for exploration of combining SHP2 and MAPK pathway inhibitors for treating KRAS-mutant cancers in the clinic.

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“…For instance, unlike CDC25activated endogenous HRas, mut HRas is no longer sensitive to the regulatory effect of the ERK-RSK1/2-NF1 positive feedback loop, which ultimately results in different ERK activation dynamics and would explain the different phenotype. 54 Additionally, structural changes on mutant HRas could result in the establishment of aberrant protein-protein interactions, 55 which may lead to the development of pathological feedback loops or crosstalks with other signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of HRas local signal transduction networks using engineered site-specific exchange factors

et al. 2018

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Ras GTPases convey signals from different types of membranes. At these locations, different Ras isoforms, interactors and regulators generate different biochemical signals and biological outputs. The study of Ras localisation-specific signal transduction networks has been hampered by our inability to specifically activate each of these Ras pools. Here, we describe a new set of site-specific tethered exchange factors, engineered by fusing the RasGRF1 CDC25 domain to sub-localisation-defining cues, whereby Ras pools at specific locations can be precisely activated. We show that the CDC25 domain has a high specificity for activating HRas but not NRas and KRas. This unexpected finding means that our constructs mainly activate endogenous HRas. Hence, their use enabled us to identify distinct pathways regulated by HRas in endomembranes and plasma membrane microdomains. Importantly, these new constructs unveil different patterns of HRas activity specified by their subcellular localisation. Overall, the targeted GEFs described herein constitute ideal tools for dissecting spatially-defined HRas biochemical and biological functions.

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Feedback activation of neurofibromin terminates growth factor-induced Ras activation

Cited by 33 publications

References 65 publications

Impairment of K‐Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR‐143

Impairment of K‐Ras signaling networks and increased efficacy of epidermal growth factor receptor inhibitors by a novel synthetic miR‐143

SHP2 Inhibition Overcomes RTK-Mediated Pathway Reactivation in KRAS-Mutant Tumors Treated with MEK Inhibitors

Characterisation of HRas local signal transduction networks using engineered site-specific exchange factors

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