ERK reinforces actin polymerization to power persistent edge protrusion during motility

Mendoza, Michelle C.; Vilela, Marco; Juarez, Jesus E.; Blenis, John; Danuser, Gaudenz

doi:10.1126/scisignal.aaa8859

Cited by 77 publications

(97 citation statements)

References 58 publications

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“…Detection of directional cues may be an important function of the EGFR signaling network. EGF gradient sensing or ERK heterogeneities have been implicated in mechanotransduction, cell polarization, and motility121314.…”

Section: Resultsmentioning

confidence: 99%

“…Unsurprisingly, dysregulated MAPK signaling underlies many cancers5. There is growing evidence that the cell fate decisions are regulated by temporal678 or even spatiotemporal profiles of ERK and RAF9101112131415. It is thus important to understand how information about the level and gradient of an extracellular stimulus is encoded and transmitted to intracellular downstream effectors.…”

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confidence: 99%

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Relaxation oscillations and hierarchy of feedbacks in MAPK signaling

Kochańczyk

Kocieniewski

Kozłowska

et al. 2017

Sci Rep

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We formulated a computational model for a MAPK signaling cascade downstream of the EGF receptor to investigate how interlinked positive and negative feedback loops process EGF signals into ERK pulses of constant amplitude but dose-dependent duration and frequency. A positive feedback loop involving RAS and SOS, which leads to bistability and allows for switch-like responses to inputs, is nested within a negative feedback loop that encompasses RAS and RAF, MEK, and ERK that inhibits SOS via phosphorylation. This negative feedback, operating on a longer time scale, changes switch-like behavior into oscillations having a period of 1 hour or longer. Two auxiliary negative feedback loops, from ERK to MEK and RAF, placed downstream of the positive feedback, shape the temporal ERK activity profile but are dispensable for oscillations. Thus, the positive feedback introduces a hierarchy among negative feedback loops, such that the effect of a negative feedback depends on its position with respect to the positive feedback loop. Furthermore, a combination of the fast positive feedback involving slow-diffusing membrane components with slower negative feedbacks involving faster diffusing cytoplasmic components leads to local excitation/global inhibition dynamics, which allows the MAPK cascade to transmit paracrine EGF signals into spatially non-uniform ERK activity pulses.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Relaxation oscillations and hierarchy of feedbacks in MAPK signaling

Kochańczyk

Kocieniewski

Kozłowska

et al. 2017

Sci Rep

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“…Our previous work on protrusion mechanics indicated that the growth of branched actin networks primarily serves the reinforcement after protrusion onset of actin assembly against mounting membrane tension (21,27). Therefore, we expected that the canonical nucleator of branched network formation, Arp2/3, would be recruited after protrusion onset and primarily after ezrin depletion.…”

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confidence: 95%

A unified role for membrane-cortex detachment during cell protrusion initiation

Welf

Miles

Huh

et al. 2019

Preprint

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Cell morphogenesis employs a diversity of membrane protrusions. They are discriminated by differences in force generation. Actin polymerization is the best studied mechanism of force generation, but growing interest in how variable molecular conditions and microenvironments alter morphogenesis has revealed other mechanisms, including intracellular pressure. Here, we show that local depletion of membrane cortex links is an essential step in the initiation of both pressure-based and actin-based protrusions. This observation challenges the quarter-century old Brownian ratchet model of actin-driven membrane protrusion, which requires an optimal balance of actin filament growth and membrane tethering. An updated model confirms membrane-filament detachment is necessary to activate the ratchet mechanism. These findings unify the regulation of different protrusion types, explaining how cells generate robust yet flexible strategies of morphogenesis. Main textCells use several mechanisms to generate the force required for membrane protrusion, with the choice of mechanism depending on cell-autonomous and environmental factors. High resolution microscopy of the molecular dynamics underlying these processes has until recently only been possible on cells adhering to glass coverslips. As a result, the most widely studied type of protrusions are the broad, flat lamellipodia that form in highly adherent cells (1). Lamellipodial protrusions are driven by actin polymerization against the plasma membrane. The persistence of this process varies widely between cell types, from tens of seconds to minutes, dependent on the efficiency of regulatory processes that upregulate the rate of monomer incorporation into the filamentous actin (f-actin) network against the resistance of the plasma membrane and the coupling of the network to substrate-anchored adhesions (2). In contrast, cells in more complex microenvironments often exhibit rounded protrusions, sometimes referred to as blebs, which are driven by intracellular pressure. Blebs form via separation of the plasma membrane from the actin cortex during a rapid expansion and typically persist for approximately 30 seconds before onset of a retraction phase that is characterized by recruitment of ezrin-radixin-moesin (ERM) family proteins and reassembly of an actin cortex (3,4). Perturbation of ERM proteins affects bleb size and frequency as well as bleb-driven migration in vivo (5,6), but this result is often ascribed to perturbations of the roles ERM proteins play in generating intracellular pressure (7,8). Other recently described protrusion mechanisms are hybrids between actin-and pressure driven mechanisms (9-11). The purely actin-driven lamellipodia and pressure-driven blebs thus represent the archetypical extremes of a wide protrusion spectrum. Especially in the context of cancer, the plasticity between lamellipodia-driven, mesenchymal migration and bleb-driven, amoeboid migration is a powerful mechanism for metastatic cells to navigate highly variable microenvironments (12). However,...

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“…The regulation of this highly dynamic and adaptable mechanism of motion dictates the outcomes of many cellular processes. For example, the stiffness of the branched actin network , the frequency of its oscillations (Mendoza et al, 2015), the relative ratio of elongation and branching (Bisi et al, 2013), and membrane trafficking (Gautier et al, 2011) can be tuned to yield distinct phenotypic effects. This regulation is achieved through a complex coordination of many signaling pathways in which RhoGTPases, small molecular switches that integrate multiple inputs to orchestrate the dynamics of the cytoskeleton, play a pivotal role.…”

Section: Introductionmentioning

confidence: 99%