Cellular and pathophysiological consequences of Arp2/3 complex inhibition: role of inhibitory proteins and pharmacological compounds

Chánez-Paredes, Sandra; Montoya-García, Armando; Schnoor, Michael

doi:10.1007/s00018-019-03128-y

Cited by 25 publications

(17 citation statements)

References 132 publications

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“…To further elucidate the underlying regulation by these specific actin arrangements to cytoplasmic CAV-1 vesicles, we employed different actin-directed drugs with specific targets (Figure 2A). Blebbistatin and CK666 inhibiting myosin II ATPase activity and Arp2/3 complex were applied, and thereby interfering with the formation of contractile and branched filament assemblies, respectively (Kovacs et al, 2004;Chanez-Paredes et al, 2019). Neither of the drugs affected the transcription and expression level of CAV-1 (Supplementary Figures 2C,D), while fluorescence imaging witnessed their expected effects on actin organization with extensive loss of prominent contractile bundles after exposure to blebbistatin and of lamellipodia after CK666 treatment, respectively (Figure 2A).…”

Section: Contractile Actin Assemblies Are Critical For the Organization And Dynamics Of Cav-1 Vesicles By Disturbing Its Phosphorylation mentioning

confidence: 99%

Feedback-Driven Mechanisms Between Phosphorylated Caveolin-1 and Contractile Actin Assemblies Instruct Persistent Cell Migration

Shi

Wen

Wang

et al. 2021

Front. Cell Dev. Biol.

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The actin cytoskeleton and membrane-associated caveolae contribute to active processes, such as cell morphogenesis and motility. How these two systems interact and control directional cell migration is an outstanding question but remains understudied. Here we identified a negative feedback between contractile actin assemblies and phosphorylated caveolin-1 (CAV-1) in migrating cells. Cytoplasmic CAV-1 vesicles display actin-associated motilities by sliding along actin filaments or/and coupling to do retrograde flow with actomyosin bundles. Inhibition of contractile stress fibers, but not Arp2/3-dependent branched actin filaments, diminished the phosphorylation of CAV-1 on site Tyr14, and resulted in substantially increased size and decreased motility of cytoplasmic CAV-1 vesicles. Reciprocally, both the CAV-1 phospho-deficient mutation on site Tyr14 and CAV-1 knockout resulted in dramatic AMPK phosphorylation, further causing reduced active level of RhoA-myosin II and increased active level of Rac1-PAK1-Cofilin, consequently led to disordered contractile stress fibers and prominent lamellipodia. As a result, cells displayed depolarized morphology and compromised directional migration. Collectively, we propose a model in which feedback-driven regulation between actin and CAV-1 instructs persistent cell migration.

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Section: Contractile Actin Assemblies Are Critical For the Organization And Dynamics Of Cav-1 Vesicles By Disturbing Its Phosphorylation mentioning

confidence: 99%

Feedback-Driven Mechanisms Between Phosphorylated Caveolin-1 and Contractile Actin Assemblies Instruct Persistent Cell Migration

Shi

Wen

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…Both WM115 (44.00; 31.00) ( Table S1 ) and WM266-4 (22.14; 76.06) [ 35 ] proteomic catalogues contain the ACTR2 /ARP2 and ACTR3 /ARP3 proteins (see also Table S10 ), which serve as major nucleators of branched-actin networks (e.g., in Lamellipodia) [ 155 , 156 , 157 ]. However, WM115 (primary) melanoma cells seem to exclusively express ARPIN (2.50) ( Table S2 ), a negative regulator of ARP2/3 activity [ 155 , 158 ], while WM266-4 (metastatic) melanoma cells can specifically synthesize WAS /WASP (0.00) and ABI2 (15.11) ( Table S3 ), two essential components of the ARP2/3 activation machinery [ 155 , 157 , 159 ]. Thereby, upregulating ARPIN or/and targeting the ARP2/3-mediated F-actin network-branching process may compel BRAF V600D metastatic melanoma cells to lose their migratory and invasive capacities.…”

Section: Resultsmentioning

confidence: 99%

From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

Giannopoulou

Velentzas

Anagnostopoulos

et al. 2021

Cancers

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Melanoma is classified among the most notoriously aggressive human cancers. Despite the recent progress, due to its propensity for metastasis and resistance to therapy, novel biomarkers and oncogenic molecular drivers need to be promptly identified for metastatic melanoma. Hence, by employing nano liquid chromatography-tandem mass spectrometry deep proteomics technology, advanced bioinformatics algorithms, immunofluorescence, western blotting, wound healing protocols, molecular modeling programs, and MTT assays, we comparatively examined the respective proteomic contents of WM115 primary (n = 3955 proteins) and WM266-4 metastatic (n = 6681 proteins) melanoma cells. It proved that WM115 and WM266-4 cells have engaged hybrid epithelial-to-mesenchymal transition/mesenchymal-to-epithelial transition states, with TGF-β controlling their motility in vitro. They are characterized by different signatures of SOX-dependent neural crest-like stemness and distinct architectures of the cytoskeleton network. Multiple signaling pathways have already been activated from the primary melanoma stage, whereas HIF1α, the major hypoxia-inducible factor, can be exclusively observed in metastatic melanoma cells. Invasion-metastasis cascade-specific sub-routines of activated Caspase-3-triggered apoptosis and LC3B-II-dependent constitutive autophagy were also unveiled. Importantly, WM115 and WM266-4 cells exhibited diverse drug response profiles, with epirubicin holding considerable promise as a beneficial drug for metastatic melanoma clinical management. It is the proteome navigation that enables systemic biomarkering and targeted drugging to open new therapeutic windows for advanced disease.

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“…Additionally, the dysfunction of endogenous inhibitory proteins of Arp2/3 also leads to the development of several diseases. For example, the over-expression of coronin 1A causes the over activation of CD4 + T cells and CD8 + T cells in aplastic anemia and hemophagocytic syndrome ( 377 ).…”

Section: Related Diseasesmentioning

confidence: 99%

The Actin Regulators Involved in the Function and Related Diseases of Lymphocytes

Sun

Zhong

et al. 2022

Front. Immunol.

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Actin is an important cytoskeletal protein involved in signal transduction, cell structure and motility. Actin regulators include actin-monomer-binding proteins, Wiskott-Aldrich syndrome (WAS) family of proteins, nucleation proteins, actin filament polymerases and severing proteins. This group of proteins regulate the dynamic changes in actin assembly/disassembly, thus playing an important role in cell motility, intracellular transport, cell division and other basic cellular activities. Lymphocytes are important components of the human immune system, consisting of T-lymphocytes (T cells), B-lymphocytes (B cells) and natural killer cells (NK cells). Lymphocytes are indispensable for both innate and adaptive immunity and cannot function normally without various actin regulators. In this review, we first briefly introduce the structure and fundamental functions of a variety of well-known and newly discovered actin regulators, then we highlight the role of actin regulators in T cell, B cell and NK cell, and finally provide a landscape of various diseases associated with them. This review provides new directions in exploring actin regulators and promotes more precise and effective treatments for related diseases.

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Cellular and pathophysiological consequences of Arp2/3 complex inhibition: role of inhibitory proteins and pharmacological compounds

Cited by 25 publications

References 132 publications

Feedback-Driven Mechanisms Between Phosphorylated Caveolin-1 and Contractile Actin Assemblies Instruct Persistent Cell Migration

Feedback-Driven Mechanisms Between Phosphorylated Caveolin-1 and Contractile Actin Assemblies Instruct Persistent Cell Migration

From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

The Actin Regulators Involved in the Function and Related Diseases of Lymphocytes

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