Defined spatiotemporal features of RAS-ERK signals dictate cell fate in MCF-7 mammary epithelial cells

Herrero, Ana; Casar, Berta; Colón-Bolea, Paula; Agudo-Ibáñez, Lorena; Crespo, Piero

doi:10.1091/mbc.e15-02-0118

Cited by 23 publications

(24 citation statements)

References 42 publications

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“…This is true at saturating (10 μM) or sub-saturating (100 nM) concentrations of these ligands, whereas saturating EGF induces no such response. In agreement with previous studies (Herrero et al, 2016; Nagashima et al, 2007), the ErbB3/ErbB4 ligand NRG1β also promotes MCF-7 cell differentiation (Figure 7A). The distinct biological response to epiregulin and epigen (compared to EGF) correlates with both sustained EGFR activation (Figure 6) and sustained Erk activation (Figure 7B).…”

Section: Resultssupporting

confidence: 93%

EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics

Freed

Bessman

Kiyatkin

et al. 2017

Cell

282

347

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Summary Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF – making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation. Our results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest parallels between partial and/or biased agonism in RTKs and G protein-coupled receptors, as well as new therapeutic opportunities for correcting RTK signaling output.

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Section: Resultssupporting

confidence: 93%

EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics

Freed

Bessman

Kiyatkin

et al. 2017

Cell

282

347

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“…While previous studies revealed that the temporal dynamics of ERK activation play a pivotal role in promoting specific cellular responses to extracellular stimuli (17,18,25), studies on the spatial activation of ERK in signal transduction has been mostly focused on its translocation to the nucleus despite the fact that ERK has hundreds of substrates in other subcellular compartments (26). For example, ERK has several known substrates near the plasma membrane, including Focal Adhesion Kinase (27) and the actin-effector WASP (6).…”

Section: Resultsmentioning

confidence: 99%

Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics

Keyes

Ganesan

Molinar‐Inglis

et al. 2019

Preprint

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A variety of different signals induce specific responses through a common, ERK-dependent kinase cascade. It has been suggested that signaling specificity can be achieved through precise temporal regulation of ERK activity. Given the wide distrubtion of ERK susbtrates across different subcellular compartments, it is important to understand how ERK activity is temporally regulated at specific subcellular locations. To address this question, we have expanded the toolbox of FRET-based ERK biosensors by creating a series of improved biosensors targeted to various subcellular regions via sequence specific motifs to measure spatiotemporal changes in ERK enzymatic activity. Using these sensors, we showed that EGF induces sustained ERK activity near the plasma membrane in sharp contrast to the transient activity observed in the cytopolasm and nucleus. Furthermore, EGF-induced plasma membrane ERK activity involves Rap1, a noncanonical activator, and controls cell morphology and EGF-induced membrane protrusion dynamics. Our work strongly supports that spatial and temporal regulation of ERK activity is integrated to control signaling specificity from a single extracellular signal to multiple cellular processes.

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“…We showed here that these mice also overexpress RACK1 in melanocytes. Thus, the difference in phenotypes could be ascribed to a differential compartmentalization of the proteins in the two melanocyte-types engaging then distinct genetic programs [26]. Alternatively, it could hint at the existence of additional pathways triggered by the NRas Q61K mutation, independent of ERK, JNK, AKT, STAT3 pathways and scaffold RACK1.…”

Section: Discussionmentioning

confidence: 99%

RACK1 cooperates with NRAS to promote melanoma in vivo

Campagne

Reyes-Gomez

Picco

et al. 2017

Cellular Signalling

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Melanoma is the deadliest skin cancer. RACK1 (Receptor for activated protein kinase C) protein was proposed as a biological marker of melanoma in human and domestic animal species harboring spontaneous melanomas. As a scaffold protein, RACK1 is able to coordinate the interaction of key signaling molecules implicated in both physiological cellular functions and tumorigenesis. A role for RACK1 in rewiring ERK and JNK signaling pathways in melanoma cell lines had been proposed. Here, we used a genetic approach to test this hypothesis in vivo in the mouse. We show that Rack1 knock-down in the mouse melanoma cell line B16 reduces invasiveness and induces cell differentiation. We have developed the first mouse model for RACK1 gain of function, Tyr::Rack1-HA transgenic mice, targeting RACK1 to melanocytes in vivo. RACK1 overexpression was not sufficient to initiate melanomas despite activated ERK and AKT. However, in a context of melanoma predisposition, RACK1 overexpression reduced latency and increased incidence and metastatic rate. In primary melanoma cells from Tyr::Rack1-HA, Tyr::NRas mice, activated JNK (c-Jun N-terminal kinase) and activated STAT3 (signal transducer and activator of transcription 3) acted as RACK1 oncogenic partners in tumoral progression. A sequential and coordinated activation of ERK, JNK and STAT3 with RACK1 is shown to accelerate aggressive melanoma development in vivo.

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Defined spatiotemporal features of RAS-ERK signals dictate cell fate in MCF-7 mammary epithelial cells

Cited by 23 publications

References 42 publications

EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics

EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics

Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics

RACK1 cooperates with NRAS to promote melanoma in vivo

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