RAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKα

Varga, Andrea; Ehrenreiter, Karin; Aschenbrenner, Bertram; Kocieniewski, Paweł; Kochańczyk, Marek; Lipniacki, Tomasz; Baccarini, Manuela

doi:10.1126/scisignal.aai8482

Cited by 43 publications

(45 citation statements)

References 53 publications

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“… 30 , 34 Point mutation in a key RAF1 dimer interface residue R401H has been shown to disrupt RAF1 dimerization with little to no effect on basal kinase activity. 35 , 36 , 37 , 38 , 39 , 40 We assessed the effect of such mutation on QKI-RAF1 (QKI-RAF1 R401H ). In co-IP assays, QKI-RAF1 R401H homodimerization with QKI-RAF1 was unaffected ( Figure 4a ) but heterodimerization with wild-type BRAF and CRAF was decreased ( Figures 4b and c ), as with wild-type QKI ( Figure 4d ) by unknown mechanisms.…”

Section: Resultsmentioning

confidence: 99%

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles

et al. 2017

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Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein–protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions.

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Section: Resultsmentioning

confidence: 99%

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles

et al. 2017

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“…Specifically, RAF1 and MEK1 are required to regulate the activity of other pathways (RHO-dependent pathways in the case of RAF1; PI3K in the case of MEK1) via protein-protein interaction ( Desideri et al., 2015 , Dorard et al., 2017 ). Intriguingly, it is the activation of the core pathway (RAF/MEK/ERK) that generates the phosphorylated forms of RAF1 and MEK1 required for the cross-talk with the RHO and with PI3K pathway, respectively ( Varga et al., 2017 , Zmajkovicova et al., 2013 ). In the case of MEK1, T292 phosphorylation promotes the formation of a ternary complex (MEK1/MAGI 100 /PTEN) required for the translocation of PTEN to the membrane, where the phosphatase turns over PIP 3 and dims signaling ( Zmajkovicova et al., 2013 ).…”

Section: Discussionmentioning

confidence: 99%

An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion

et al. 2018

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SummaryHematopoietic stem cells (HSCs) sustain hematopoiesis throughout life. HSCs exit dormancy to restore hemostasis in response to stressful events, such as acute blood loss, and must return to a quiescent state to prevent their exhaustion and resulting bone marrow failure. HSC activation is driven in part through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTORC1 signaling pathway, but less is known about the cell-intrinsic pathways that control HSC dormancy. Here, we delineate an ERK-dependent, rate-limiting feedback mechanism that controls HSC fitness and their re-entry into quiescence. We show that the MEK/ERK and PI3K pathways are synchronously activated in HSCs during emergency hematopoiesis and that feedback phosphorylation of MEK1 by activated ERK counterbalances AKT/mTORC1 activation. Genetic or chemical ablation of this feedback loop tilts the balance between HSC dormancy and activation, increasing differentiated cell output and accelerating HSC exhaustion. These results suggest that MEK inhibitors developed for cancer therapy may find additional utility in controlling HSC activation.

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“…These proteins control different cellular functions. For example RAF-1, interacts with ROKα implicated in the reorganization of cytoskeletal filaments [26] and with MST2/LATS pathway controlling apoptosis [27].…”

Section: Discussionmentioning

confidence: 99%

Limits to the rate of information transmission through MAPK pathway

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et al. 2018

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Two important signaling pathways of NF-κB and ERK transmit merely one bit of information about the level of extracellular stimulation. It is thus unclear how such systems can coordinate complex cell responses to external cues. Here, we analyze information transmission in the MAPK/ERK pathway that features relaxation oscillations and responds to EGF by pulses of activated ERK. Based on an experimentally verified computational model of the MAPK/ERK pathway, we demonstrate that when input sequences of EGF pulses are transcoded to output sequences of ERK activity pulses, transmitted information increases nearly linearly with time. Moreover, the information channel capacity C (defined as the upper limit of information that can be transmitted over a sufficiently long time t, divided by t), is not limited by the bandwidth B = 1/τ, where τ ≈ 1 hour is the relaxation time. Specifically, when input is provided in the form of sequences of short binary EGF pulses separated by varying intervals that are multiples of τ/n (but are not shorter than τ), then for n = 2, C ≈ 1.39 bit/hour; and for n = 4, C ≈ 1.86 bit/hour. We hypothesize that the primary mode of operation of the MAPK pathway is to translate extracellular growth factor "bursts" into precisely timed intracellular ERK "spikes" of a predefined amplitude. Such pulse-interval transcoding allows to relay more information than the amplitude-amplitude transcoding considered previously for the ERK and NF-κB pathways. Author summaryTo coordinate their actions, cells communicate with each other by sending, receiving, and interpreting cytokine signals. Cells recognize chemical identity of signaling molecules and process quantitative and temporal properties of stimulation: amplitude, duration, or frequency. Previous studies indicated that the MAPK pathway transmits about one bit of information about the amplitude (concentration) of a stimulating cytokine, EGF. Sending more information may be enabled by temporal signal modulation.Here, we use the conceptual framework of information theory to support a hypothesis that the MAPK pathway, analyzed as a noisy information channel, reaches maximum information transmission rate when receiving sequences of EGF pulses that are transcoded to sequences of activity pulses of an effector kinase of the pathway, ERK. Since the pathway resetting time is about 1 hour, one could expect that-when sending EGF pulses of "0" or "1" amplitude every hour-the pathway is able transmit up to 1 bit per hour. We show, however, that when EGF pulses are separated by intervals that are not shorter than 1 hour and are multiples of 15 min (60, 75, 90 min, etc.), information rate can be nearly 2 bits per hour. We hypothesize that high information rate is necessary to control cell proliferation and motility.

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RAF1/BRAF dimerization integrates the signal from RAS to ERK and ROKα

Cited by 43 publications

References 53 publications

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles

CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles

An ERK-Dependent Feedback Mechanism Prevents Hematopoietic Stem Cell Exhaustion

Limits to the rate of information transmission through MAPK pathway

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