Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration

Law, Ah-Lai; Jalal, Shamsinar; Pallett, Tommy; Mosis, Fuad; Guni, Ahmad; Brayford, Simon; Yolland, Lawrence; Marcotti, Stefania; Levitt, James A.; Poland, Simon P.; Rowe-Sampson, Maia; Jandke, Anett; Köchl, Robert; Pula, Giordano; Ameer-Beg, Simon; Stramer, Brian; Krause, Matthias

doi:10.1038/s41467-021-25916-6

Cited by 24 publications

(31 citation statements)

References 42 publications

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“…5 a). Because of the distinct subcellular distribution of Rac1 in DB cells, immunocytochemistry was performed to detect the subcellular distribution of WAVE2 47 . Confocal microscopy revealed that WAVE2 was found to be localized to the cell periphery and co-localized with F-actin fibers and in WT and DKO cells, as illustrated by the increase of white pixels in merged images (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction

Xing

Huang

Kunkemoeller

et al. 2022

Sci Rep

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Fibroblasts are a major cell population that perform critical functions in the wound healing process. In response to injury, they proliferate and migrate into the wound space, engaging in extracellular matrix (ECM) production, remodeling, and contraction. However, there is limited knowledge of how fibroblast functions are altered in diabetes. To address this gap, several state-of-the-art microscopy techniques were employed to investigate morphology, migration, ECM production, 2D traction, 3D contraction, and cell stiffness. Analysis of cell-derived matrix (CDM) revealed that diabetic fibroblasts produce thickened and less porous ECM that hindered migration of normal fibroblasts. In addition, diabetic fibroblasts were found to lose spindle-like shape, migrate slower, generate less traction force, exert limited 3D contractility, and have increased cell stiffness. These changes were due, in part, to a decreased level of active Rac1 and a lack of co-localization between F-actin and Waskott-Aldrich syndrome protein family verprolin homologous protein 2 (WAVE2). Interestingly, deletion of thrombospondin-2 (TSP2) in diabetic fibroblasts rescued these phenotypes and restored normal levels of active Rac1 and WAVE2-F-actin co-localization. These results provide a comprehensive view of the extent of diabetic fibroblast dysfunction, highlighting the regulatory role of the TSP2-Rac1-WAVE2-actin axis, and describing a new function of TSP2 in regulating cytoskeleton organization.

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Section: Resultsmentioning

confidence: 99%

Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction

Xing

Huang

Kunkemoeller

et al. 2022

Sci Rep

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“…This included Hjurp , which can regulate double-strand DNA repair ( 32 – 34 ), neurogenesis factors Dll3 and Arx ( 35 , 36 ), as well as neuronal cell migration regulator Nhsl1 a (Fig. 5D and data S22) ( 37 ). Thus, in addition to its oncogenic mutator functions via sequence-specific somatic mutagenesis, Pgbd5 may also regulate neuronal progenitor cell development and DNA damage repair.…”

Section: Resultsmentioning

confidence: 99%

Childhood cancer mutagenesis caused by transposase-derived PGBD5

Yamada,

Keller,

Gutierrez

et al. 2024

Sci. Adv.

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Genomic rearrangements are a hallmark of most childhood tumors, including medulloblastoma, one of the most common brain tumors in children, but their causes remain largely unknown. Here, we show that PiggyBac transposable element derived 5 (Pgbd5) promotes tumor development in multiple developmentally accurate mouse models of Sonic Hedgehog (SHH) medulloblastoma. Most Pgbd5-deficient mice do not develop tumors, while maintaining normal cerebellar development. Ectopic activation of SHH signaling is sufficient to enforce cerebellar granule cell progenitor–like cell states, which exhibit Pgbd5-dependent expression of distinct DNA repair and neurodevelopmental factors. Mouse medulloblastomas expressing Pgbd5 have increased numbers of somatic structural DNA rearrangements, some of which carry PGBD5-specific sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. This identifies PGBD5 as a medulloblastoma mutator and provides a genetic mechanism for the generation of oncogenic DNA rearrangements in childhood cancer.

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“…Thus, targeting Rac1-Scar/Wave-Arp2/3 would help to inhibit tumor progression. Another study shows that Rac1-Scar/Wave-Arp2/3 can be negatively regulated by Nance-Horan Syndrome-like 1 protein (NHSL1), which directly interacts with Scar/Wave, thus reducing cell lamellipodia stability and migration efficiency [ 94 ]. As a local inhibitor of lamellipodia induced by Scar/Wave, CYFIP-related Rac interactor (CYRI) can compete with Scar/Wave to bind Rac1, which is important in regulating pseudopod complexity and dynamics [ 95 ].…”

Section: Molecular Mechanisms Of Cell Migration Regulated By Rac1mentioning

confidence: 99%

Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy

Luo

et al. 2023

Molecules

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Cell migration is crucial for physiological and pathological processes such as morphogenesis, wound repair, immune response and cancer invasion/metastasis. There are many factors affecting cell migration, and the regulatory mechanisms are complex. Rac1 is a GTP-binding protein with small molecular weight belonging to the Rac subfamily of the Rho GTPase family. As a key molecule in regulating cell migration, Rac1 participates in signal transduction from the external cell to the actin cytoskeleton and promotes the establishment of cell polarity which plays an important role in cancer cell invasion/metastasis. In this review, we firstly introduce the molecular structure and activity regulation of Rac1, and then summarize the role of Rac1 in cancer invasion/metastasis and other physiological processes. We also discuss the regulatory mechanisms of Rac1 in cell migration and highlight it as a potential target in cancer therapy. Finally, the current state as well as the future challenges in this area are considered. Understanding the role and the regulatory mechanism of Rac1 in cell migration can provide fundamental insights into Rac1-related cancer progression and further help us to develop novel intervention strategies for cancer therapy in clinic.

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Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration

Cited by 24 publications

References 42 publications

Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction

Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction

Childhood cancer mutagenesis caused by transposase-derived PGBD5

Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy

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