Multifaceted Rho GTPase Signaling at the Endomembranes

Phuyal, Santosh; Farhan, Hesso

doi:10.3389/fcell.2019.00127

Cited by 92 publications

(86 citation statements)

References 83 publications

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“…The canonical picture states that activated RhoA is restricted at plasma membrane (Garcia-Mata et al, 2011; Hodge and Ridley, 2016). While transmembrane receptor trafficking, such as for integrins or cadherins, has been under intense scrutiny in the context of cell migration and cancer metastasis (Mellman and Yarden, 2013; Paul et al, 2015; Kajiho et al, 2018), the link between traffic and Rho GTPases is only now coming to the fore and our data support the new idea that “endosomes serve as a hub for Rho GTPase activation and spatiotemporal signal generation” (Phuyal and Farhan, 2019). Recent studies highlighted the presence of active Rho GTPases in intracellular membranes and argue for an origin of Rho signaling from the endosomal network (Phuyal and Farhan, 2019).…”

Section: Discussionsupporting

confidence: 66%

Endosomal spatio-temporal modulation of the cortical RhoA zone conditions epithelial cell organization

Gaston

Beco

Doss

et al. 2020

Preprint

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SummaryAt the basis of cell shape and behavior, actomyosin organization and force-generating property are widely studied, however very little is known about the regulation of the contractile network in space and time. Here we study the role of the epithelial-specific protein EpCAM, a contractility modulator, in cell shape and motility, and we show that it is required for the maturation of stress fibers and frontrear polarity acquisition at the single cell level. There, EpCAM ensures the remodeling of a transient active RhoA zone in the cortex of spreading epithelial cells. GTP-RhoA follows the endosomal pathway mediated by Rab35 and EHD1, where it co-evolves together with EpCAM. In fact, EpCAM balances GTP-RhoA turnover in order to tune actomyosin remodeling for cell shape, polarity and mechanical property acquisition. Impairment of GTP-RhoA endosomal trafficking either by EpCAM silencing or Rab35 / EHD1 mutant expression prevents correct myosin-II activity, stress fiber formation, and ultimately cell polarization. Collectively, this work shows that the coupling of EpCAM/RhoA co-trafficking to actomyosin rearrangement is critical for spreading, and advances our understanding of how biochemical and mechanical properties can be coupled for cell plasticity.

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Section: Discussionsupporting

confidence: 66%

Endosomal spatio-temporal modulation of the cortical RhoA zone conditions epithelial cell organization

Gaston

Beco

Doss

et al. 2020

Preprint

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“…As described above, Rac1 and Cdc42 GTPases transduce TCR signals driving actin cytoskeleton remodeling during immunological synapse formation. These molecules were shown to be associated with vesicles in other cellular types (Phuyal and Farhan, 2019). Interestingly, we observed that a minor fraction of Rac1 in T cells colocalizes with Rab11 + recycling endosomes, whereas most of the Rac1 protein seems to be associated with the plasma membrane or diffused in the cytosol.…”

Section: Vesicle Traffic Controls Tcr Signaling and The Cytoskeletonmentioning

confidence: 66%

Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration, Activation, and Effector Functions

Mastrogiovanni

Juzans

Alcover

et al. 2020

Front. Cell Dev. Biol.

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Dynamic localization of receptors and signaling molecules at the plasma membrane and within intracellular vesicular compartments is crucial for T lymphocyte sensing environmental cues, triggering membrane receptors, recruiting signaling molecules, and fine-tuning of intracellular signals. The orchestrated action of actin and microtubule cytoskeleton and intracellular vesicle traffic plays a key role in all these events that together ensure important steps in T cell physiology. These include extravasation and migration through lymphoid and peripheral tissues, T cell interactions with antigen-presenting cells, T cell receptor (TCR) triggering by cognate antigen-major histocompatibility complex (MHC) complexes, immunological synapse formation, cell activation, and effector functions. Cytoskeletal and vesicle traffic dynamics and their interplay are coordinated by a variety of regulatory molecules. Among them, polarity regulators and membrane-cytoskeleton linkers are master controllers of this interplay. Here, we review the various ways the T cell plasma membrane, receptors, and their signaling machinery interplay with the actin and microtubule cytoskeleton and with intracellular vesicular compartments. We highlight the importance of this fine-tuned crosstalk in three key stages of T cell biology involving cell polarization: T cell migration in response to chemokines, immunological synapse formation in response to antigen cues, and effector functions. Finally, we discuss two examples of perturbation of this interplay in pathological settings, such as HIV-1 infection and mutation of the polarity regulator and tumor suppressor adenomatous polyposis coli (Apc) that leads to familial polyposis and colorectal cancer.

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“…Such specialized roles may reflect selective activation of different intracellular pools of Rac1, which would depend on Rac-GEFs localized at discrete locations. Crucially, Rac1 can be expressed and activated in a range of intracellular compartments, including the nucleus, endosomes and mitochondria, and a similar scenario has been described for Rac-GEFs (Justilien et al, 2017;Abdrabou and Wang, 2018;Pan et al, 2018;Phuyal and Farhan, 2019). One interesting example is the activation of rRNA synthesis and tumorigenesis in the nucleolus of lung cancer cells by the GEF Ect2, thus implicating Rac1 in ribosomal biogenesis (Justilien et al, 2017), a process associated with tumor growth, EMT and metastasis (Prakash et al, 2019).…”

Section: Location Is the Key: Why Do Cancer Cells Need Multiple Rac-gmentioning

confidence: 74%

Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer

Cooke

Baker

Kazanietz

2020

Front. Cell Dev. Biol.

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Lung cancer is the leading cause of cancer-related deaths worldwide, with nonsmall cell lung cancer (NSCLC) representing ∼85% of new diagnoses. The disease is often detected in an advanced metastatic stage, with poor prognosis and clinical outcome. In order to escape from the primary tumor, cancer cells acquire highly motile and invasive phenotypes that involve the dynamic reorganization of the actin cytoskeleton. These processes are tightly regulated by Rac1, a small G-protein that participates in the formation of actin-rich membrane protrusions required for cancer cell motility and for the secretion of extracellular matrix (ECM)-degrading proteases. In this perspective article we focus on the mechanisms leading to aberrant Rac1 signaling in NSCLC progression and metastasis, highlighting the role of Rac Guanine nucleotide Exchange Factors (GEFs). A plausible scenario is that specific Rac-GEFs activate discrete intracellular pools of Rac1, leading to unique functional responses in the context of specific oncogenic drivers, such as mutant EGFR or mutant KRAS. The identification of dysregulated Rac signaling regulators may serve to predict critical biomarkers for metastatic disease in lung cancer patients, ultimately aiding in refining patient prognosis and decision-making in the clinical setting.

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Multifaceted Rho GTPase Signaling at the Endomembranes

Cited by 92 publications

References 83 publications

Endosomal spatio-temporal modulation of the cortical RhoA zone conditions epithelial cell organization

Endosomal spatio-temporal modulation of the cortical RhoA zone conditions epithelial cell organization

Coordinating Cytoskeleton and Molecular Traffic in T Cell Migration, Activation, and Effector Functions

Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer

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