Strength Through Unity: The Power of the Mega-Scaffold MACF1

Cusseddu, Rebecca; Ahrends, Robert; Côté, Jean‐François

doi:10.3389/fcell.2021.641727

Cited by 16 publications

(18 citation statements)

References 79 publications

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“…The aim of this study was to summarize the proteins important for cytoskeletal crosstalk in humans and to explore the evolutionary background of the proteins found at the intersections of the cytoskeletal datasets. The spectraplakin protein dystonin emerged from the analysis as the only protein found in all datasets examined, consistent with previous work asserting the role of spectraplakin proteins in cytoskeletal crosstalk [ 27 , 28 ]. Based on our analysis, it appears that complete spectraplakin proteins, comprising the necessary domains for interaction with all components of the cytoskeleton, arose first in Bilateria ( Figure 4 E).…”

Section: Discussionsupporting

confidence: 87%

“…The overlapping of the retrieved datasets displayed only one common protein, dystonin (DST, also known as BPAG1 or BP230) ( Figure 1 ). Together with a microtubule-associated crosslinking factor 1 (MACF1) DST belongs to the spectraplakin family of proteins, a family of cytoskeletal regulators capable of binding different types of cytoskeletal filaments [ 27 , 28 ]. This is achieved through different binding modules present in these proteins.…”

Section: Resultsmentioning

confidence: 99%

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Ancient Origins of Cytoskeletal Crosstalk: Spectraplakin-like Proteins Precede the Emergence of Cortical Microtubule Stabilization Complexes as Crosslinkers

Paradžik

Podgorski

Zeljko

et al. 2022

IJMS

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Adhesion between cells and the extracellular matrix (ECM) is one of the prerequisites for multicellularity, motility, and tissue specialization. Focal adhesions (FAs) are defined as protein complexes that mediate signals from the ECM to major components of the cytoskeleton (microtubules, actin, and intermediate filaments), and their mutual communication determines a variety of cellular processes. In this study, human cytoskeletal crosstalk proteins were identified by comparing datasets with experimentally determined cytoskeletal proteins. The spectraplakin dystonin was the only protein found in all datasets. Other proteins (FAK, RAC1, septin 9, MISP, and ezrin) were detected at the intersections of FAs, microtubules, and actin cytoskeleton. Homology searches for human crosstalk proteins as queries were performed against a predefined dataset of proteomes. This analysis highlighted the importance of FA communication with the actin and microtubule cytoskeleton, as these crosstalk proteins exhibit the highest degree of evolutionary conservation. Finally, phylogenetic analyses elucidated the early evolutionary history of spectraplakins and cortical microtubule stabilization complexes (CMSCs) as model representatives of the human cytoskeletal crosstalk. While spectraplakins probably arose at the onset of opisthokont evolution, the crosstalk between FAs and microtubules is associated with the emergence of metazoans. The multiprotein complexes contributing to cytoskeletal crosstalk in animals gradually gained in complexity from the onset of metazoan evolution.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Ancient Origins of Cytoskeletal Crosstalk: Spectraplakin-like Proteins Precede the Emergence of Cortical Microtubule Stabilization Complexes as Crosslinkers

Paradžik

Podgorski

Zeljko

et al. 2022

IJMS

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“…The transport mechanism requires transiently binding passive cross-linkers that bind the microtubule end via EB proteins. The most prominent examples of such cross-linkers are the spectraplakins and drebrin [13,18]. In this work, we used an engineered cross-linker TipAct that contains the actinand microtubule end-binding domains of ACF7 (also known as MACF1).…”

Section: Discussionmentioning

confidence: 99%

“…The most prominent and best-studied member is ACF7 (MACF1) and its Drosophila homologue Short stop (Shot), which contain both microtubule latticeand end-binding activities. These cross-linkers play a crucial role in a number of cellular processes, such as cell migration, cell-cell connections, vesicular transport, cell polarity and cell division [10,13]. In addition to ACF7, also other passive cross-linking proteins such as tau and Gas2Like1 have been shown to result in co-alignment and stabilization of the actin and microtubule networks [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Cross-linkers at growing microtubule ends generate forces that drive actin transport

Alkemade

Wierenga

Volkov

et al. 2021

Preprint

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The actin and microtubule cytoskeletons form active networks in the cell that can contract and remodel, resulting in vital cellular processes as cell division and motility. Motor proteins play an important role in generating the forces required for these processes, but more recently the concept of passive cross-linkers being able to generate forces has emerged. So far, these passive cross-linkers have been studied in the context of separate actin and microtubule systems. Here, we show that crosslinkers also allow actin and microtubules to exert forces on each other. More specifically, we study single actin filaments that are cross-linked to growing microtubule ends, using in vitro reconstitution, computer simulations, and a minimal theoretical model. We show that microtubules can transport actin filaments over large (micrometer-range) distances, and find that this transport results from two antagonistic forces arising from the binding of cross-linkers to the overlap between the actin and microtubule filaments. The cross-linkers attempt to maximize the overlap between the actin and the tip of the growing microtubules, creating an affinity-driven forward condensation force, and simultaneously create a competing friction force along the microtubule lattice. We predict and verify experimentally how the average transport time depends on the actin filament length and the microtubule growth velocity, confirming the competition between a forward condensation force and a backward friction force. In addition, we theoretically predict and experimentally verify that the condensation force is of the order of 0.1 pN. Thus, our results reveal a new mechanism for local actin remodelling by growing microtubules.

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“…Among the most frequently mutated genes, we identi ed several genes directly or indirectly implicated in cell motility. These included MUC16 (82% of the samples), which encodes a large cell surface protein and is best known as a biomarker (CA-125) for ovarian cancer 30 , MACF1 (60%), which encodes a large intracellular protein that bridges actin and microtubule laments 31 , and FAT1 (57%), FAT3 (55%) and FAT4, which encode three members of the cadherin family of transmembrane proteins previously implicated in the regulation of cell motility 32 (Fig. 4d).…”

Section: Identi Cation Of Nsclc-bm Driving Mutationsmentioning

confidence: 99%

Comparative genomic profiling identifies targetable brain metastasis drivers in non-small cell lung cancer

Nicoś

Harbers

Patrucco

et al. 2022

Preprint

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Brain metastases (BM) severely impact the prognosis and quality of life of patients with non-small cell lung cancer (NSCLC). To identify targetable drivers of NSCLC-BM, we profiled somatic copy number alterations (SCNAs) in 51 matched pairs of primary NSCLC and BM samples from 33 patients with lung adenocarcinoma (LUAD) and 18 patients with lung squamous cell carcinoma (LUSC). BM consistently had a higher burden of SCNAs compared to the matched primary tumors, and SCNAs were typically homogeneously distributed within BM, as revealed by multi-region SCNA profiling in 15 BM samples, suggesting that BM do not undergo extensive evolution once formed. By comparing focal SCNAs in matched NSCLC-BM pairs, we identified BM driving alterations affecting multiple cancer genes, including several targetable genes such as CDK12, DDR2, ERBB2, and NTRK1, which we validated in an independent cohort of 84 BM samples. We explored the metastatic potential of CDK12 and DDR2 in vitro and in vivo and found that overexpression of either gene alone in murine lung cancer cells causes the induction of key genes involved in epithelial-mesenchymal transition. Finally, we performed whole-exome sequencing of 40 NSCLC-BM pairs and identified BM driver mutations in multiple cancer genes, including several genes involved in epigenome editing and 3D genome organization, such as EP300, CTCF, and STAG2, which we validated by targeted sequencing of an independent cohort of 115 BM samples. Our study represents the most comprehensive genomic characterization of LUAD and LUSC BM available to date, uncovering potentially targetable NSCLC-BM drivers and inspiring the design of novel precision treatment strategies for NSCLC patients.

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Strength Through Unity: The Power of the Mega-Scaffold MACF1

Cited by 16 publications

References 79 publications

Ancient Origins of Cytoskeletal Crosstalk: Spectraplakin-like Proteins Precede the Emergence of Cortical Microtubule Stabilization Complexes as Crosslinkers

Ancient Origins of Cytoskeletal Crosstalk: Spectraplakin-like Proteins Precede the Emergence of Cortical Microtubule Stabilization Complexes as Crosslinkers

Cross-linkers at growing microtubule ends generate forces that drive actin transport

Comparative genomic profiling identifies targetable brain metastasis drivers in non-small cell lung cancer

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