аналитика - Cell Biology - # Caveolae-mediated mechanotransduction in migrating cells

Rapid Disassembly and Reassembly of Caveolae in Response to Changes in Membrane Tension Regulates Cell Migration

Q: How do caveolae regulate the activities of Ect2, ROCK, and ARHGAP29 to control cycles of caveolae assembly/disassembly and actomyosin contractility at the cell rear?

Caveolae play a crucial role in regulating mechanotransduction by responding to changes in membrane tension. In the context of cell rear retraction during migration, caveolae are involved in a feedback loop with RhoA/ROCK1 signaling. When membrane tension is low, caveolae formation at the cell rear is promoted, which is dependent on RhoA/ROCK1 signaling, Ect2, and PKN2. This leads to F-actin alignment, actomyosin contractility, and rapid rear retraction. Loss of caveolae, increased membrane tension, or inhibition of Rho signaling disrupt this positive feedback loop, inhibiting rear retraction and impeding cell migration. The molecular mechanisms by which caveolae regulate the activities of Ect2, ROCK, and ARHGAP29 involve a dynamic interplay between these proteins. ROCK is recruited to caveolae at high membrane tension, and its activity is required for caveolae reassembly after hypo-osmotic shock. On the other hand, ARHGAP29, a RhoGAP, is associated with caveolae at low membrane tension and inhibits caveolae rear localization and cell migration when overexpressed. This suggests that Ect2/ROCK and ARHGAP29 have opposing functions in caveolae formation and actomyosin contractility at the cell rear. The spatio-temporal coordination of these proteins allows for the regulation of cycles of caveolae assembly/disassembly and actomyosin contractility, ultimately influencing cell rear retraction during migration.

Q: How do the findings from this study on caveolae-mediated mechanotransduction in 2D migrating cells translate to 3D migration in complex tissue environments?

The findings from this study on caveolae-mediated mechanotransduction in 2D migrating cells provide valuable insights that can be extrapolated to 3D migration in complex tissue environments. In both 2D and 3D migration, the rear of migrating cells exhibits a front-rear gradient in membrane tension, with caveolae playing a critical role in sensing and responding to these mechanical cues. The dynamic caveolae-associated protein network identified in this study, enriched in cortical actin regulators and focal adhesion proteins, is highly sensitive to changes in membrane tension. In complex tissue environments, such as during development or in pathological conditions like cancer metastasis, cells encounter diverse mechanical cues that influence their migration behavior. The regulation of caveolae assembly/disassembly, actomyosin contractility, and cell rear retraction by membrane tension and the associated protein network is likely to be crucial for efficient 3D migration. The spatio-temporal coordination of caveolae with the actin cytoskeleton and signaling molecules like ROCK and ARHGAP29 may play a significant role in guiding cell migration through complex tissue environments. Understanding the mechanisms of caveolae-mediated mechanotransduction in 2D migrating cells can provide a framework for studying and manipulating cell migration in 3D contexts.

Q: What are the potential mechanisms by which caveolae inhibit ARHGAP29 expression and YAP signaling?

Caveolae are involved in a complex interplay with ARHGAP29 and YAP signaling, influencing cell migration and mechanotransduction pathways. The potential mechanisms by which caveolae inhibit ARHGAP29 expression and YAP signaling can be elucidated based on the findings of the study: Inhibition of Rho/ROCK Signaling: Caveolae regulate the activities of Rho/ROCK signaling, which are known to be involved in the regulation of ARHGAP29 expression. By modulating Rho/ROCK activity, caveolae can indirectly influence the expression levels of ARHGAP29. YAP Regulation: YAP signaling is interconnected with caveolae function, as YAP controls caveolar gene transcription and formation. Caveolae negatively regulate YAP, which in turn can impact the expression of ARHGAP29. The inhibition of YAP signaling by caveolae may lead to decreased ARHGAP29 expression. Caveolae-Mediated Signaling Pathways: Caveolae are involved in various signaling pathways that can impact gene expression and protein regulation. The dynamic caveolae-associated protein network identified in the study may contain key components that modulate ARHGAP29 expression and YAP signaling. Membrane Tension Sensing: Caveolae act as mechanosensitive membrane reservoirs that sense changes in membrane tension. Alterations in membrane tension can trigger signaling cascades that regulate gene expression, including the expression of ARHGAP29 and the activity of YAP. Overall, the inhibition of ARHGAP29 expression and YAP signaling by caveolae is likely mediated through a combination of direct and indirect mechanisms involving signaling pathways, membrane tension sensing, and the dynamic interplay between caveolae and key regulatory proteins. Further research is needed to fully elucidate the specific molecular mechanisms underlying these interactions.

Основные понятия

Caveolae act as a dynamic membrane reservoir that senses and responds to changes in membrane tension, coupling this to the regulation of actomyosin contractility and cell migration.

Аннотация

The study used time-resolved proximity proteomics with APEX2 to define the caveolae-associated protein network in migrating RPE1 cells under normal conditions and in response to an acute increase in membrane tension induced by hypo-osmotic shock.

Key insights:

Caveolae are abundant and stably associated with the rear of migrating RPE1 cells, providing a suitable model to study caveolae-mediated mechanotransduction.
The caveolae interactome is enriched in cortical actin regulators and focal adhesion proteins, and is highly sensitive to changes in membrane tension.
Membrane tension regulates the association of ROCK and the RhoGAP ARHGAP29 with caveolae. ARHGAP29 controls caveolae rear localization and RPE1 cell migration.
Caveolae in turn regulate ARHGAP29 expression, likely through the control of YAP signaling, suggesting a feedback loop between caveolae and Rho/ROCK-mediated actomyosin contractility at the cell rear.
The data provide a framework for dissecting the molecular mechanisms underlying caveolae-regulated mechanotransduction pathways in migrating cells.

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biorxiv.org

Статистика

Caveolae are abundant at the rear of migrating RPE1 cells.
Caveolae disassemble in response to acute hypo-osmotic shock and reassemble upon recovery.
ROCK activity is required for caveolae reassembly after hypo-osmotic shock.
Overexpression of ARHGAP29 displaces caveolae from the cell rear and impairs RPE1 cell migration.

Цитаты

"Caveolae act as a dynamic membrane reservoir that senses and responds to changes in membrane tension, coupling this to the regulation of actomyosin contractility and cell migration."
"The caveolae interactome is enriched in cortical actin regulators and focal adhesion proteins, and is highly sensitive to changes in membrane tension."
"ARHGAP29 controls caveolae rear localization and RPE1 cell migration."

Ключевые выводы из

Time-resolved proximity proteomics uncovers a membrane tension-sensitive caveolin-1 interactome at the rear of migrating cells

by Girardello,R... в www.biorxiv.org 12-14-2022

https://www.biorxiv.org/content/10.1101/2022.12.13.520222v1

Дополнительные вопросы

How do caveolae regulate the activities of Ect2, ROCK, and ARHGAP29 to control cycles of caveolae assembly/disassembly and actomyosin contractility at the cell rear?

Caveolae play a crucial role in regulating mechanotransduction by responding to changes in membrane tension. In the context of cell rear retraction during migration, caveolae are involved in a feedback loop with RhoA/ROCK1 signaling. When membrane tension is low, caveolae formation at the cell rear is promoted, which is dependent on RhoA/ROCK1 signaling, Ect2, and PKN2. This leads to F-actin alignment, actomyosin contractility, and rapid rear retraction. Loss of caveolae, increased membrane tension, or inhibition of Rho signaling disrupt this positive feedback loop, inhibiting rear retraction and impeding cell migration.
The molecular mechanisms by which caveolae regulate the activities of Ect2, ROCK, and ARHGAP29 involve a dynamic interplay between these proteins. ROCK is recruited to caveolae at high membrane tension, and its activity is required for caveolae reassembly after hypo-osmotic shock. On the other hand, ARHGAP29, a RhoGAP, is associated with caveolae at low membrane tension and inhibits caveolae rear localization and cell migration when overexpressed. This suggests that Ect2/ROCK and ARHGAP29 have opposing functions in caveolae formation and actomyosin contractility at the cell rear. The spatio-temporal coordination of these proteins allows for the regulation of cycles of caveolae assembly/disassembly and actomyosin contractility, ultimately influencing cell rear retraction during migration.

How do the findings from this study on caveolae-mediated mechanotransduction in 2D migrating cells translate to 3D migration in complex tissue environments?

The findings from this study on caveolae-mediated mechanotransduction in 2D migrating cells provide valuable insights that can be extrapolated to 3D migration in complex tissue environments. In both 2D and 3D migration, the rear of migrating cells exhibits a front-rear gradient in membrane tension, with caveolae playing a critical role in sensing and responding to these mechanical cues. The dynamic caveolae-associated protein network identified in this study, enriched in cortical actin regulators and focal adhesion proteins, is highly sensitive to changes in membrane tension.
In complex tissue environments, such as during development or in pathological conditions like cancer metastasis, cells encounter diverse mechanical cues that influence their migration behavior. The regulation of caveolae assembly/disassembly, actomyosin contractility, and cell rear retraction by membrane tension and the associated protein network is likely to be crucial for efficient 3D migration. The spatio-temporal coordination of caveolae with the actin cytoskeleton and signaling molecules like ROCK and ARHGAP29 may play a significant role in guiding cell migration through complex tissue environments. Understanding the mechanisms of caveolae-mediated mechanotransduction in 2D migrating cells can provide a framework for studying and manipulating cell migration in 3D contexts.

What are the potential mechanisms by which caveolae inhibit ARHGAP29 expression and YAP signaling?

Caveolae are involved in a complex interplay with ARHGAP29 and YAP signaling, influencing cell migration and mechanotransduction pathways. The potential mechanisms by which caveolae inhibit ARHGAP29 expression and YAP signaling can be elucidated based on the findings of the study:

Inhibition of Rho/ROCK Signaling: Caveolae regulate the activities of Rho/ROCK signaling, which are known to be involved in the regulation of ARHGAP29 expression. By modulating Rho/ROCK activity, caveolae can indirectly influence the expression levels of ARHGAP29.

YAP Regulation: YAP signaling is interconnected with caveolae function, as YAP controls caveolar gene transcription and formation. Caveolae negatively regulate YAP, which in turn can impact the expression of ARHGAP29. The inhibition of YAP signaling by caveolae may lead to decreased ARHGAP29 expression.

Caveolae-Mediated Signaling Pathways: Caveolae are involved in various signaling pathways that can impact gene expression and protein regulation. The dynamic caveolae-associated protein network identified in the study may contain key components that modulate ARHGAP29 expression and YAP signaling.

Membrane Tension Sensing: Caveolae act as mechanosensitive membrane reservoirs that sense changes in membrane tension. Alterations in membrane tension can trigger signaling cascades that regulate gene expression, including the expression of ARHGAP29 and the activity of YAP.

Overall, the inhibition of ARHGAP29 expression and YAP signaling by caveolae is likely mediated through a combination of direct and indirect mechanisms involving signaling pathways, membrane tension sensing, and the dynamic interplay between caveolae and key regulatory proteins. Further research is needed to fully elucidate the specific molecular mechanisms underlying these interactions.