Affinage

NHSL1

NHS-like protein 1 · UniProt Q5SYE7

Length
1610 aa
Mass
170.7 kDa
Annotated
2026-06-10
19 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NHSL1 is a regulator of actin-based cell protrusion and migration that operates as a direct binding partner of the Scar/WAVE complex at lamellipodia leading edges (PMID:34584076). It associates with the Scar/WAVE complex through the Abi SH3 domain via two binding sites, and active Rac1 binds NHSL1 at two regions that target it to the leading edge (PMID:34584076). The functional output of NHSL1 is isoform-dependent: the F1 isoform negatively regulates migration by reducing Arp2/3 activity, decreasing lamellipodial F-actin density, and impairing lamellipodia stability (PMID:34584076), whereas the A isoform forms an alternative complex (the NHSL1-A complex) carrying its own WCA domain that recruits and activates Arp2/3 in a GSK3-phosphorylation-dependent manner to promote migration speed and chemotaxis (PMID:40161727). NHSL1 also defines a WAVE Shell Complex that contains PPP2R1A and substitutes for the Scar/WAVE subunit, with NHSL1 acting downstream of PPP2R1A to control migration persistence (PMID:37322026). Beyond migration, NHSL1 promotes fast endophilin-mediated endocytosis at the leading edge through direct interactions with endophilin A2 and Ena/VASP proteins, enhancing actin polymerisation at FEME sites [PMID:bio_10.1101_2024.10.23.619882]. Its in vivo role in tuning protrusion dynamics and actin retrograde flow is conserved, as the zebrafish ortholog nhsl1b controls protrusion length, lifetime, and migration persistence during gastrulation (PMID:40021913).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2010 Medium

    Before NHSL1 itself was functionally studied, the founding family member NHS was shown to engage the WAVE regulatory machinery, establishing the NHS/NHSL family as actin-cytoskeleton regulators that interface with the WAVE complex.

    Evidence Co-IP of the NHS WAVE homology domain with Abi, HSPC300, Nap1, and Sra1, plus knockdown/overexpression phenotypes on the actin cytoskeleton

    PMID:20332100

    Open questions at the time
    • Performed on NHS, not NHSL1 directly
    • Did not establish whether NHSL1 activates or inhibits Arp2/3
  2. 2021 High

    Established that NHSL1 directly binds the Scar/WAVE complex and, unexpectedly, acts as a negative regulator of Arp2/3 activity and lamellipodial stability, defining NHSL1 as a brake on cell migration.

    Evidence Co-IP with domain mapping, FRET-FLIM Arp2/3 biosensor, live-cell imaging and siRNA in mammalian cells

    PMID:34584076

    Open questions at the time
    • Did not resolve which NHSL1 isoform mediates inhibition
    • Mechanism of Arp2/3 down-regulation at the molecular level not defined
  3. 2023 High

    Identified an alternative WAVE Shell Complex in which NHSL1 replaces the Scar/WAVE subunit and recruits PPP2R1A, and placed NHSL1 genetically downstream of PPP2R1A in controlling migration persistence.

    Evidence Proteomics, reciprocal Co-IP, genetic epistasis via NHSL1 depletion, Rac1-dependent actin polymerisation assays, and tumor-mutation analysis

    PMID:37322026

    Open questions at the time
    • Catalytic role of the PP2A scaffold subunit within the complex not defined
    • Relationship between the WSC and isoform-specific outputs unresolved
  4. 2025 Medium

    Resolved the isoform paradox by showing the NHSL1-A isoform carries an SHD that builds a Scar/WAVE-like complex and a GSK3-phosphorylated WCA domain that recruits and activates Arp2/3, converting NHSL1 into a positive driver of migration speed and chemotaxis.

    Evidence Domain deletion/mutagenesis, Co-IP, GSK3 kinase assay, and migration/chemotaxis assays (preprint)

    PMID:40161727

    Open questions at the time
    • Preprint, not peer-reviewed
    • Structural basis of WCA-Arp2/3 activation not solved
    • How A and F1 isoform activities are balanced in a single cell unclear
  5. 2025 Medium

    Demonstrated in vivo that NHSL1 function in tuning protrusion dynamics and actin retrograde flow is conserved and physiologically required for collective cell migration during development.

    Evidence Zebrafish nhsl1b loss- and gain-of-function with live imaging and F-actin flow measurement during gastrulation

    PMID:40021913

    Open questions at the time
    • Does not distinguish which mammalian isoform the zebrafish role corresponds to
    • WAVE-complex partnership in vivo not directly tested
  6. 2024 Medium

    Extended NHSL1 function beyond protrusion regulation to membrane trafficking by showing it drives fast endophilin-mediated endocytosis via direct multivalent EndoA2 and Ena/VASP binding.

    Evidence Direct binding/pulldown assays, co-localisation, siRNA, and FEME uptake plus actin polymerisation measurements at FEME sites (preprint)

    PMID:bio_10.1101_2024.10.23.619882

    Open questions at the time
    • Preprint, single lab
    • Link between FEME role and WAVE-complex role at the leading edge not integrated
    • Does not control dynamin recruitment

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the opposing F1 (inhibitory) and A (activating) isoforms are spatiotemporally coordinated, and how the migration and endocytosis functions are mechanistically linked at the leading edge, remains unresolved.
  • No structural model of either NHSL1-containing complex
  • Switching between inhibitory and activating modes uncharacterized
  • Upstream signals controlling isoform usage unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1266738 Developmental Biology 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
ABI1ARPCPPP2R1ARAC1SH3GL1VASP
Complex memberships
NHSL1-A complexScar/WAVE complexWAVE Shell Complex (WSC)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 NHSL1 directly binds the Scar/WAVE complex, co-localising at protruding lamellipodia; this interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. Active Rac1 binds NHSL1 at two regions that mediate its leading-edge targeting. NHSL1 inhibits cell migration by reducing Arp2/3 activity (measured by FRET-FLIM biosensor), decreasing F-actin density in lamellipodia and impairing lamellipodia stability. Co-immunoprecipitation, FRET-FLIM Arp2/3 biosensor, live-cell imaging, siRNA knockdown, domain-mapping pulldowns Nature communications High 34584076
2023 PPP2R1A associates with an alternative form of the WAVE complex called the WAVE Shell Complex (WSC), which contains NHSL1 instead of the Arp2/3-activating subunit WAVE/Scar. PPP2R1A is required for migration persistence in random and directed migration, and this requirement is abolished by NHSL1 depletion, placing NHSL1 downstream of PPP2R1A in the WSC. Tumor-associated PPP2R1A mutations impair WSC binding and migration regulation. Proteomics/mass spectrometry, co-immunoprecipitation, siRNA knockdown, cell migration assays, RAC1-dependent actin polymerisation assay in cell extracts Nature communications High 37322026
2025 The NHSL1-A isoform contains a Scar homology domain (SHD) that is sufficient to form an 'NHSL1-A complex' containing the same subunits as the Scar/WAVE complex but with NHSL1-A replacing Scar/WAVE. NHSL1-A also contains a WCA domain that interacts with and recruits the Arp2/3 complex; this WCA domain is phosphorylated by GSK3, which increases Arp2/3 interaction. Unlike the NHSL1-F1 isoform, the NHSL1-A complex promotes cell migration speed and chemotaxis via increased lamellipodial Arp2/3 activity. Domain deletion/mutagenesis, co-immunoprecipitation, kinase assay (GSK3 phosphorylation), cell migration assays, chemotaxis assay bioRxivpreprint Medium 40161727
2025 In zebrafish gastrulation, nhsl1b localises to the tips of actin-rich protrusions in migrating mesodermal cells and controls protrusion dynamics: loss of nhsl1b reduces protrusion length and lifetime and increases F-actin assembly rate and retrograde flow, while overexpression has the opposite effect, resulting in impaired cell speed and migration persistence in vivo. Loss-of-function (morpholino/mutant), gain-of-function (overexpression), live imaging, F-actin flow measurement, zebrafish gastrulation assay Communications biology Medium 40021913
2024 NHSL1 directly and multivalently interacts with endophilin A2 (EndoA2) and also binds Ena/VASP actin-elongation proteins. NHSL1 localises to FEME vesicular puncta and promotes fast endophilin-mediated endocytosis (FEME); its interactions with both EndoA2 and Ena/VASP are required for this function. NHSL1 enhances actin polymerisation at FEME sites but does not control dynamin recruitment. Co-localisation (fluorescence microscopy), direct binding/pulldown assays, siRNA knockdown of NHSL1, FEME uptake assay, actin polymerisation measurement at FEME sites bioRxivpreprint Medium bio_10.1101_2024.10.23.619882
2010 NHS, the founding member of the NHS/NHSL1/NHSL2 protein family, contains a functional WAVE homology domain (WHD) in its N-terminus that interacts with Abi family proteins, HSPC300, Nap1, and Sra1 — components of the WAVE regulatory complex. NHS localises to sites of cell–cell contact, lamellipodia leading edges, and focal adhesions, and its knockdown disrupts the actin cytoskeleton and circumferential actin ring, causing increased cell spreading, while overexpression inhibits lamellipod formation. Co-immunoprecipitation (NHS WHD with WAVE complex subunits), siRNA knockdown, overexpression, fluorescence localisation Human molecular genetics Medium 20332100
2004 NHSL1 (GUKH2/KIAA1357) was identified as a paralog of NHS (GUKH1), sharing eight conserved GUKH homology (GKH1–GKH8) domains and a proline-rich domain, with 28.5% amino-acid identity. NHSL1 and NHS map to paralogous duplicated chromosomal regions (6q24 and Xp22, respectively), establishing NHSL1 as a member of the NHS gene family. Bioinformatics/sequence analysis, genomic structure determination, expression profiling by RT-PCR International journal of oncology Low 15010845

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The Nance-Horan syndrome protein encodes a functional WAVE homology domain (WHD) and is important for co-ordinating actin remodelling and maintaining cell morphology. Human molecular genetics 62 20332100
2011 Identification of MST1/STK4 and SULF1 proteins as autoantibody targets for the diagnosis of colorectal cancer by using phage microarrays. Molecular & cellular proteomics : MCP 59 21228115
2004 Identification of the gene for Nance-Horan syndrome (NHS). Journal of medical genetics 53 15466011
2012 An optimized predictor panel for colorectal cancer diagnosis based on the combination of tumor-associated antigens obtained from protein and phage microarrays. Journal of proteomics 41 22465712
2004 Identification and characterization of human GUKH2 gene in silico. International journal of oncology 37 15010845
2015 Analysis of microarray-identified genes and microRNAs associated with drug resistance in ovarian cancer. International journal of clinical and experimental pathology 31 26261572
2020 Exome sequencing of 112 trios identifies recessive genetic variants in brain arteriovenous malformations. Journal of neurointerventional surgery 26 32848021
2021 Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration. Nature communications 25 34584076
2020 Integrative genomic analysis of salivary duct carcinoma. Scientific reports 20 32929114
2023 PPP2R1A regulates migration persistence through the NHSL1-containing WAVE Shell Complex. Nature communications 14 37322026
2015 Whole exome sequencing in a case of sporadic multiple meningioma reveals shared NF2, FAM109B, and TPRXL mutations, together with unique SMARCB1 alterations in a subset of tumor nodules. Cancer genetics 14 25981829
2016 A genome-wide association study of essential hypertension in an Australian population using a DNA pooling approach. Molecular genetics and genomics : MGG 13 27866268
2025 Unraveling breast cancer response to neoadjuvant chemotherapy through integrated genomic, transcriptomic, and circulating tumor DNA analysis. Breast cancer research : BCR 6 40312292
2021 Proteogenomics Integrating Novel Junction Peptide Identification Strategy Discovers Three Novel Protein Isoforms of Human NHSL1 and EEF1B2. Journal of proteome research 6 34420305
2025 Nance-Horan-syndrome-like 1b controls mesodermal cell migration by regulating protrusion and actin dynamics during zebrafish gastrulation. Communications biology 3 40021913
2022 High-resolution melt analysis for the detection of skin/sweat via DNA methylation. Electrophoresis 2 36480207
2025 MicroRNA-3145 as a potential therapeutic target for hepatitis B virus: inhibition of viral replication via downregulation of HBS and HBX. Frontiers in microbiology 1 39834379
2025 The NHSL1-A complex interacts with the Arp2/3 complex and controls cell migration efficiency and chemotaxis. bioRxiv : the preprint server for biology 0 40161727
2025 Gene polymorphisms associated with corneal curvature, astigmatism and its vector components in children. Eye and vision (London, England) 0 41320768

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