Interdependence between EGFR and Phosphatases Spatially Established by Vesicular Dynamics Generates a Growth Factor Sensing and Responding Network

Stanoev, Angel; Mhamane, Amit; Schuermann, Klaus C.; Grecco, Hernán E.; Stallaert, Wayne; Baumdick, Martin; Brüggemann, Yannick; Joshi, Maitreyi Sadanand; Roda-Navarro, Pedro; Fengler, Sven; Stockert, Rabea; Roßmannek, Lisaweta; Luig, Jutta; Koseska, Aneta; Bastiaens, Philippe I. H.

doi:10.1016/j.cels.2018.06.006

Cited by 45 publications

(136 citation statements)

References 60 publications

(89 reference statements)

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“…Systems that sense time‐varying signals require memory in order to integrate the signal information (Hochreiter & Schmidhuber, ). A minimal cellular sensing network that accounts for memory in receptor activity (R a ) is a two‐component toggle switch (Fig A), where the double‐negative feedback (DNF) interaction (Reynolds et al , ; Tischer & Bastiaens, ; Stanoev et al , ) between the active receptor and an inactivating enzyme (e.g. a phosphatase), P DNF,a , follows the law of mass action:

\begin{matrix} \frac{normald R_{a}}{normald t} & = k_{R} [R_{i} (α_{1} R_{i} + α_{2} R_{a} + α_{3} L R_{a}) - {\overset{γ}{true}}_{italicDNF} P_{D N F, a} R_{a}] \\ \frac{normald P_{D N F, a}}{normald t} & = k_{1} [P_{D N F, i} - k_{2 / 1} P_{D N F, a} - {\overset{β}{true}}_{italicDNF} P_{D N F, a} (R_{a} + L R_{a})] \end{matrix}

…”

Section: Resultsmentioning

confidence: 99%

“…These results indicate that both the long‐ and the short‐term memory that result from the presence of stable attractors do not fulfil the conditions necessary for processing time‐varying inputs. The long‐term memory is not transient and thereby it will inhibit responsiveness to upcoming cues (Stanoev et al , ), whereas the short‐term memory only corresponds to the growth factor dose that activates the system and is not reflected in the temporal receptor activity profile.…”

Section: Resultsmentioning

confidence: 99%

“…Receptor activity dynamics, on the other hand, is not only influenced by ligand binding dynamics, but rather reflects the dynamics of the biochemical network in which the receptor is embedded (Stanoev et al , ). Non‐trivial dynamical solutions can hereby emerge, in particular due to recurrent interactions between the network components (Reynolds et al , ; Tischer & Bastiaens, ).…”

Section: Introductionmentioning

confidence: 99%

“…In a broad range of biological systems, positive feedback interactions give rise to bistable dynamics, which is considered to underlie memory features (Xiong & Ferrell, ; Wang et al , ; Burrill & Silver, ; Doncic et al , ). However, signal‐induced switching between basal and high receptor activity states, and thereby permanent memory formation, limits response to upcoming stimuli (Stanoev et al , ). To overcome equivalent limitations of stable states, information processing in the context of real‐time computations of sensory stimuli by neural microcircuits, universal frameworks using transient dynamics and state‐dependent trajectories have been proposed (Maass et al , ; Durstewitz, ; Jaeger & Haas, ).…”

Section: Introductionmentioning

confidence: 99%

“…Using single‐molecule reaction–diffusion simulations on the other hand, we depict how such dynamic memory can be realized on molecular level. Based on the experimental findings that the epidermal growth factor receptor (EGFR) system operates at critical organization (Stanoev et al , ), we propose a fluctuation‐sensing mechanism as a basis for self‐organized maintenance at the critical region and discuss its limitations. We further discuss why organization at criticality represents a generic dynamical mechanism which enables processing of time‐varying growth factor signals by cell surface receptors.…”

Section: Introductionmentioning

confidence: 99%

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Organization at criticality enables processing of time‐varying signals by receptor networks

Stanoev

Nandan

Koseska

2020

Molecular Systems Biology

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How cells utilize surface receptors for chemoreception is a recurrent question spanning between physics and biology over the past few decades. However, the dynamical mechanism for processing time‐varying signals is still unclear. Using dynamical systems formalism to describe criticality in non‐equilibrium systems, we propose generic principle for temporal information processing through phase space trajectories using dynamic transient memory. In contrast to short‐term memory, dynamic memory generated via “ghost” attractor enables signal integration depending on stimulus history and thereby uniquely promotes integrating and interpreting complex temporal growth factor signals. We argue that this is a generic feature of receptor networks, the first layer of the cell that senses the changing environment. Using the experimentally established epidermal growth factor sensing system, we propose how recycling could provide self‐organized maintenance of the critical receptor concentration at the plasma membrane through a simple, fluctuation‐sensing mechanism. Processing of non‐stationary signals, a feature previously attributed only to neural networks, thus uniquely emerges for receptor networks organized at criticality.

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\begin{matrix} \frac{normald R_{a}}{normald t} & = k_{R} [R_{i} (α_{1} R_{i} + α_{2} R_{a} + α_{3} L R_{a}) - {\overset{γ}{true}}_{italicDNF} P_{D N F, a} R_{a}] \\ \frac{normald P_{D N F, a}}{normald t} & = k_{1} [P_{D N F, i} - k_{2 / 1} P_{D N F, a} - {\overset{β}{true}}_{italicDNF} P_{D N F, a} (R_{a} + L R_{a})] \end{matrix}

…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Organization at criticality enables processing of time‐varying signals by receptor networks

Stanoev

Nandan

Koseska

2020

Molecular Systems Biology

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The physical basis of analog‐to‐digital signal processing in the EGFR system—Delving into the role of the endoplasmic reticulum

Kreplin,

Arumugam

2024

BioEssays

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Receptor tyrosine kinases exhibit ligand‐induced activity and uptake into cells via endocytosis. In the case of epidermal growth factor (EGF) receptor (EGFR), the resulting endosomes are trafficked to the perinuclear region, where dephosphorylation of receptors occurs, which are subsequently directed to degradation. Traveling endosomes bearing phosphorylated EGFRs are subjected to the activity of cytoplasmic phosphatases as well as interactions with the endoplasmic reticulum (ER). The peri‐nuclear region harbors ER‐embedded phosphatases, a component of the EGFR‐bearing endosome‐ER contact site. The ER is also emerging as a central player in spatiotemporal control of endosomal motility, positioning, tubulation, and fission. Past studies strongly suggest that the physical interaction between the ER and endosomes forms a reaction “unit” for EGFR dephosphorylation. Independently, endosomes have been implicated to enable quantization of EGFR signals by modulation of the phosphorylation levels. Here, we review the distinct mechanisms by which endosomes form the logistical means for signal quantization and speculate on the role of the ER.

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The effects of CD148 Q276P/R326Q polymorphisms in A431D epidermoid cancer cell proliferation and epidermal growth factor receptor signaling

Takahashi

Pašić

et al. 2021

Cancer Reports

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Background CD148 is a transmembrane protein tyrosine phosphatase that is expressed in multiple cell types. Previous studies have shown that CD148 dephosphorylates growth factor receptors and their signaling molecules, including EGFR and ERK1/2, and negatively regulates cancer cell growth. Furthermore, research of clinical patients has shown that highly linked CD148 gene polymorphisms, Gln276Pro (Q276P) and Arg326Gln (R326Q), are associated with an increased risk of several types of cancer. However, the biological effects of these missense mutations have not been studied. Aim We aimed to determine the biological effects of CD148 Q276P/R326Q mutations in cancer cell proliferation and growth factor signaling, with emphasis on EGFR signaling. Methods CD148 forms, wild‐type (WT) or Q276P/R326Q, were retrovirally introduced into A431D epidermoid carcinoma cells that lacks CD148 expression. The stable cells that express comparable levels of CD148 were sorted by flow cytometry. A431D cells infected with empty retrovirus was used as a control. CD148 localization, cell proliferation rate, EGFR signaling, and the response to thrombospondin‐1 (TSP1), a CD148 ligand, were assessed by immunostaining, cell proliferation assay, enzyme‐linked immunosorbent assay, and Western blotting. Results Both CD148 forms (WT, Q276P/R326Q) were distributed to cell surface and all three cell lines expressed same level of EGFR. Compared to control cells, the A431D cells that express CD148 forms showed significantly lower cell proliferation rates. EGF‐induced EGFR and ERK1/2 phosphorylation as well as cell proliferation were also significantly reduced in these cells. Furthermore, TSP1 inhibited cell proliferation in CD148 (WT, Q276P/R326Q)‐expressing A431D cells, while it showed no effects in control cells. However, significant differences were not observed between CD148 WT and Q276P/R326Q cells. Conclusion Our data demonstrates that Q276P/R326Q mutations do not have major effects on TSP1‐CD148 interaction as well as on CD148's cellular localization and activity to inhibit EGFR signaling and cell proliferation.

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Interdependence between EGFR and Phosphatases Spatially Established by Vesicular Dynamics Generates a Growth Factor Sensing and Responding Network

Cited by 45 publications

References 60 publications

Organization at criticality enables processing of time‐varying signals by receptor networks

Organization at criticality enables processing of time‐varying signals by receptor networks

The physical basis of analog‐to‐digital signal processing in the EGFR system—Delving into the role of the endoplasmic reticulum

The effects of CD148 Q276P/R326Q polymorphisms in A431D epidermoid cancer cell proliferation and epidermal growth factor receptor signaling

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