Affinage

HCLS1

Hematopoietic lineage cell-specific protein · UniProt P14317

Length
486 aa
Mass
54.0 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HCLS1 (HS1) is a hematopoietic-specific actin-regulatory adaptor protein that couples antigen receptor and chemokine receptor signaling to Arp2/3-complex-mediated actin polymerization, governing immune synapse formation, cell migration, adhesion, endocytosis, and both proliferative and apoptotic responses in lymphocytes, platelets, neutrophils, NK cells, and dendritic cells (PMID:7641686, PMID:16782030, PMID:17579181, PMID:18587398, PMID:22031761). Upon receptor engagement, Syk phosphorylates HS1 at Tyr397, creating an SH2 docking site for Src-family kinases (Lyn, Lck, c-Fgr) that then phosphorylate Tyr222 and Tyr378 in a sequential two-kinase mechanism; these phosphotyrosines recruit distinct effectors—Vav1, Nck, ARHGEF1, PLCγ1—to drive actin remodeling, with Tyr397 selectively controlling adhesion/cytolysis and Tyr378 controlling chemotaxis (PMID:8611520, PMID:10066823, PMID:15795233, PMID:18587398, PMID:25359136, PMID:28465529). HS1 directly binds F-actin via its coiled-coil domain and activates the Arp2/3 complex via its repeat domain to promote branched actin nucleation, while CK2-mediated Ser/Thr phosphorylation potentiates tyrosine phosphorylation and protects HS1 from caspase-3 cleavage during apoptosis (PMID:12534372, PMID:16157603, PMID:10806407, PMID:11689006). HS1 also binds LEF-1 and transports it into the nucleus to sustain granulopoiesis downstream of G-CSF; defective HS1 phosphorylation in HAX1-mutant severe congenital neutropenia patients impairs this pathway, and HCLS1-deficient mice are neutropenic (PMID:23001182).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1993 High

    Identification of HS1 as a major tyrosine kinase substrate in BCR signaling and its association with Lyn established the protein as a signaling node downstream of the B-cell antigen receptor, opening the question of its functional role.

    Evidence Protein purification, peptide microsequencing, and reciprocal Co-IP from anti-IgM-stimulated B cells

    PMID:7682714

    Open questions at the time
    • No functional phenotype yet assigned
    • Kinase-substrate relationship not mechanistically dissected
    • Downstream effectors unknown
  2. 1995 High

    Gene-targeted knockout and rescue experiments demonstrated that HS1 is essential for antigen receptor-induced clonal expansion and clonal deletion of lymphocytes, establishing that it is not merely a phosphorylation substrate but a required signal transducer for both proliferative and apoptotic outcomes of receptor engagement.

    Evidence HS1-knockout mice with proliferation/apoptosis assays; reconstitution of apoptosis sensitivity in HS1-deficient WEHI-231 B cells

    PMID:7638185 PMID:7641686

    Open questions at the time
    • Mechanism by which HS1 controls apoptosis versus proliferation not resolved
    • Phosphorylation site requirements not mapped
  3. 1996 High

    Reconstitution of a sequential two-kinase phosphorylation mechanism—Syk performs primary phosphorylation creating SH2 docking sites for Src-family kinases that carry out secondary phosphorylation—resolved how HS1 integrates signals from distinct kinase families and revealed that SH2-phosphotyrosine docking, not catalytic-site specificity, governs the reaction order.

    Evidence In vitro kinase assays with phosphopeptide competition; Co-IP of Lck/Fyn SH2 and SH3 domains with HS1 in T cells

    PMID:8611520 PMID:8943564

    Open questions at the time
    • Specific tyrosine residues not yet identified
    • In vivo significance of sequential phosphorylation not tested
  4. 1997 High

    Identification of Tyr378 and Tyr397 as the functionally critical phosphosites (required for BCR-induced apoptosis and nuclear translocation) and discovery of the HS1–HAX-1 interaction linked HS1 phosphorylation to specific cellular outcomes and to mitochondrial/survival signaling.

    Evidence Site-directed mutagenesis with apoptosis and localization readouts; yeast two-hybrid, reciprocal Co-IP, and confocal co-localization for HAX-1

    PMID:9058808 PMID:9104825

    Open questions at the time
    • Which kinase phosphorylates which site in vivo unresolved
    • HAX-1 functional significance for HS1 not tested by loss-of-function
  5. 1999 High

    Mass spectrometry identification of Tyr222 as the Src-family kinase target site, and demonstration that complex dissociation follows secondary phosphorylation, revealed a self-limiting phosphorylation cycle that explained how HS1 could transiently integrate signals then release its kinase.

    Evidence MS-based peptide identification combined with in vitro kinase reconstitution and kinetic analysis

    PMID:10066823

    Open questions at the time
    • Functional consequence of Tyr222 phosphorylation not yet tested in cells
    • Downstream effectors recruited by each phosphosite not identified
  6. 2000 Medium

    Discovery that CK2 phosphorylates HS1 on Ser/Thr residues and that this potentiates subsequent tyrosine phosphorylation introduced a cross-talk mechanism between constitutive and activation-induced phosphorylation cascades.

    Evidence In vitro CK2 kinase assays with deleted HS1 forms, okadaic acid and CK2 inhibitor treatment in platelets

    PMID:10806407

    Open questions at the time
    • Specific Ser/Thr sites not mapped
    • In vivo CK2 requirement not demonstrated by genetic approach
    • Structural basis of potentiation unknown
  7. 2001 High

    Demonstration that caspase-3 cleaves HS1 at defined sites during apoptosis, and that CK2 phosphorylation protects against this cleavage, revealed a regulatory switch determining whether HS1 promotes survival signaling or is degraded during cell death.

    Evidence In vitro caspase cleavage assays, cell-based apoptosis with CK2 inhibitor TBB and multiple apoptotic stimuli

    PMID:11689006 PMID:11988074

    Open questions at the time
    • Physiological relevance of caspase cleavage in immune cell selection not tested in vivo
    • Relative contributions of the two cleavage site clusters unknown
  8. 2003 High

    Direct binding of HS1 to purified Arp2/3 complex and F-actin, with quantitative affinities and demonstration of branched actin nucleation activity, established HS1 as a bona fide actin nucleation-promoting factor rather than merely a signaling scaffold.

    Evidence Recombinant protein binding assays (Kd measurements), pyrene actin polymerization, immunofluorescence co-localization

    PMID:12534372

    Open questions at the time
    • Domain requirements for Arp2/3 activation not yet mapped
    • Relative contribution versus cortactin/N-WASP not addressed
  9. 2005 High

    Domain dissection showing that the coiled-coil region binds F-actin and the repeat domain binds Arp2/3, with synergistic activation, defined the minimal structural architecture enabling HS1's nucleation-promoting function and cortical localization.

    Evidence Deletion mutagenesis with in vitro F-actin cosedimentation, Arp2/3 nucleation assay, and live-cell GFP imaging

    PMID:16157603

    Open questions at the time
    • No high-resolution structural data for HS1–Arp2/3 interface
    • How phosphorylation regulates domain function not addressed
  10. 2005 High

    Ordered Syk→Lyn phosphorylation at Tyr397→Tyr222 was recapitulated in platelets with phosphosite-specific antibodies, extending the two-kinase mechanism beyond B cells and demonstrating that phosphorylation-dependent plasma membrane translocation drives platelet cytoskeletal rearrangement.

    Evidence Pharmacological inhibitors, phosphosite-specific antibodies, Co-IP, and immunofluorescence in thrombin-stimulated human platelets

    PMID:15795233

    Open questions at the time
    • No platelet-specific KO phenotype yet
    • Downstream platelet effectors not identified
  11. 2006 High

    HS1-knockout T cells revealed that HS1 is essential for F-actin accumulation and stability at the immune synapse, for Ca²⁺ influx, and for IL-2 transcription; phosphotyrosine-dependent recruitment of Vav1 to the IS established the link between HS1 phosphorylation and Rac/Rho GTPase activation at the synapse.

    Evidence HS1-KO T cells with live-cell actin imaging, Ca²⁺ flux, IL-2 reporter, phosphomutant re-expression, Co-IP

    PMID:16782030

    Open questions at the time
    • How HS1 stabilizes versus initiates synapse actin not distinguished
    • Relative contribution of individual phosphosites in T cells not separated
  12. 2007 High

    HS1-null mice showed increased bleeding times and impaired platelet aggregation/secretion downstream of GPVI and PAR-4, establishing HS1 as functionally required for hemostasis and placing it in the GPVI→Syk→HS1 signaling axis in platelets.

    Evidence HS1-KO mouse platelet aggregation, secretion, bleeding time, FeCl₃ thrombosis model, Co-IP with Syk and PI3K

    PMID:17579181

    Open questions at the time
    • Specific actin-dependent platelet process (spreading, clot retraction, secretion) controlled by HS1 not fully dissected
  13. 2008 High

    Separation-of-function analysis in NK cells demonstrated that Tyr397 selectively controls adhesion and cytolysis while Tyr378 controls chemotaxis, revealing that individual phosphotyrosines on HS1 recruit distinct effector complexes to drive different cellular outputs from the same scaffold.

    Evidence HS1 knockdown in NK cells with phosphosite-specific mutant re-expression; cytolysis, adhesion, and chemotaxis assays

    PMID:18587398

    Open questions at the time
    • Identity of the effectors uniquely recruited by each phosphosite in NK cells not determined
    • Whether this phosphosite-function separation generalizes to all hematopoietic cells unknown
  14. 2010 High

    HS1 was shown to control CLL cell migration, adhesion, and in vivo homing, and HS1 loss in the Eμ-TCL1 mouse model accelerated disease, indicating that HS1's cytoskeletal functions restrain CLL progression—likely by retaining leukemic cells in tissue microenvironments.

    Evidence HS1 siRNA in CLL cells, HS1-KO mouse B cells, in vivo xenograft, Eμ-TCL1 × HS1-KO survival

    PMID:20530793

    Open questions at the time
    • Mechanism by which HS1 loss accelerates CLL not resolved at molecular level
    • Whether HS1 phosphorylation status differs in indolent versus aggressive CLL not tested
  15. 2011 High

    HS1 was found to be required specifically for receptor-mediated endocytosis (not phagocytosis or macropinocytosis) in dendritic cells, interacting with dynamin-2 to support endocytic invaginations necessary for antigen cross-presentation, extending HS1's actin-regulatory role to membrane trafficking.

    Evidence HS1-KO DCs with endocytosis/phagocytosis/macropinocytosis assays, Co-IP with dynamin-2, EM of endocytic intermediates

    PMID:22031761

    Open questions at the time
    • How HS1-Arp2/3 activity is directed specifically to endocytic sites unknown
    • Whether HS1 phosphorylation is required for endocytosis not tested
  16. 2012 High

    Two studies expanded HS1's role to granulopoiesis and neutrophil chemotaxis: HS1 binds LEF-1 and transports it into the nucleus to sustain G-CSF-driven granulopoiesis (defective in HAX1-mutant neutropenia patients), and phosphorylated HS1 regulates Rac activation, Vav1 phosphorylation, and Arp2/3 interaction to drive directional neutrophil migration.

    Evidence Co-IP of HCLS1–LEF-1, nuclear translocation assays, HAX1-mutant patient cells, HCLS1-KO mice neutropenia; HS1 KD in neutrophil-like cells with phosphomutant rescue, Rac/Vav1 assays

    PMID:22679023 PMID:23001182

    Open questions at the time
    • Mechanism of HS1-mediated LEF-1 nuclear import not resolved
    • Whether HAX-1 directly regulates HS1 phosphorylation or acts indirectly unknown
  17. 2013 High

    LYN-mediated HS1-Tyr397 phosphorylation was identified as a driver of enhanced cytoskeletal function (migration, adhesion, F-actin) and survival in a subset of CLL patients, and dasatinib inhibition abrogated this axis, providing a pharmacologically targetable mechanism linking HS1 phosphorylation to disease pathogenesis.

    Evidence Phosphosite-specific antibodies, dasatinib inhibition, siRNA, migration/adhesion assays, Eμ-TCL1 transplant model

    PMID:23325840

    Open questions at the time
    • Patient stratification criteria for LYN-active CLL not standardized
    • Downstream transcriptional consequences of ERK activation via HS1 not explored
  18. 2014 Medium

    Discovery that CXCR4/SDF1α signaling induces Tyr378 phosphorylation of HS1 to recruit Nck via its SH2 domain, promoting actin polymerization and T cell migration, identified a specific phosphosite–effector pairing downstream of chemokine receptors.

    Evidence Co-IP, siRNA knockdown of HS1 and Nck, actin polymerization and migration assays in T cells

    PMID:25359136

    Open questions at the time
    • Kinase responsible for Tyr378 phosphorylation downstream of CXCR4 not identified
    • Whether Nck recruitment is direct or via an intermediate not fully resolved
  19. 2017 High

    Two studies placed HS1 in new signaling contexts: Wnt5a/ROR1 recruits HS1 via ROR1's proline-rich domain to activate ARHGEF1/RhoA and enhance CLL motility, and HS1-KO neutrophils showed defective Rac1→Rap1 activation required for LFA-1-dependent adhesion and extravasation in vivo.

    Evidence ROR1 domain mutants and Co-IP with HS1/ARHGEF1 in CLL cells; intravital microscopy of HS1-KO neutrophils, GTPase activation assays

    PMID:28122813 PMID:28465529

    Open questions at the time
    • How HS1 bridges ROR1 to ARHGEF1 structurally unknown
    • Whether Rac1→Rap1 cascade is HS1-dependent in cell types beyond neutrophils not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural basis of HS1–Arp2/3 and HS1–F-actin interactions at atomic resolution; the identity of the kinase(s) phosphorylating HS1 downstream of chemokine receptors; how phosphosite-specific effector selection (Vav1 vs. Nck vs. ARHGEF1) is determined; and whether HS1's nuclear role with LEF-1 involves direct transcriptional regulation.
  • No high-resolution structure of HS1 or its complexes available
  • Phosphosite-to-effector selectivity code not defined
  • Nuclear function beyond LEF-1 transport uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 8 GO:0008092 cytoskeletal protein binding 5
Localization
GO:0005856 cytoskeleton 5 GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 10 R-HSA-162582 Signal Transduction 7 R-HSA-5357801 Programmed Cell Death 4 R-HSA-109582 Hemostasis 2 R-HSA-1266738 Developmental Biology 1
Partners
ACTR2DNM2HAX1LEF1LYNNCK1SYKVAV1
Complex memberships
Arp2/3 complex (functional partner, not stable subunit)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 HS1 (p75HS1) was identified as a major substrate of protein-tyrosine kinases in B-cell antigen receptor signaling, undergoing rapid tyrosine phosphorylation and associating with the Src-like kinase Lyn after crosslinking of membrane-bound IgM. Protein purification, peptide microsequencing, immunoprecipitation, Western blot Proceedings of the National Academy of Sciences of the United States of America High 7682714
1995 HS1-deficient mice generated by gene targeting showed impaired antigen receptor-induced clonal expansion of B and T cells and defective clonal deletion (thymic negative selection and peritoneal B cell apoptosis), establishing HS1 as essential for antigen receptor signaling pathways leading to both proliferation and apoptosis. Gene targeting (knockout mice), proliferation assays, apoptosis assays, crossing with TCR transgenic mice The EMBO journal High 7641686
1995 Re-expression of HS1 in an anti-IgM-resistant WEHI-231 variant (which had dramatically reduced HS1 levels) restored sensitivity to BCR-mediated apoptosis, demonstrating HS1 is required downstream of BCR for the apoptotic signal. Expression vector transfection, apoptosis assay Proceedings of the National Academy of Sciences of the United States of America High 7638185
1996 p72Syk phosphorylates HS1 at sites containing motifs recognized by SH2 domains of Src kinases; this primary phosphorylation converts HS1 into a substrate for Src-family kinases (c-Fgr, Lyn, Fyn), which carry out secondary phosphorylation via SH2-domain-mediated docking. This sequential two-kinase mechanism requires SH2-phosphotyrosine interaction, not catalytic-site recognition. In vitro kinase assay, phosphopeptide competition, co-immunoprecipitation Biochemistry High 8611520
1996 Lck SH3 domain binds HS1 constitutively via its proline-rich region, while the Lck SH2 domain associates with HS1 only upon TCR stimulation (after tyrosine phosphorylation); Fyn SH2 similarly binds phospho-HS1 upon TCR stimulation but Fyn SH3 does not interact. Co-immunoprecipitation, domain-binding analysis in T cell lines International immunology Medium 8943564
1997 HS1 interacts directly with HAX-1 (a novel mitochondrial/ER/nuclear envelope protein); association is mediated by the N-terminal region of HS1 and the C-terminal half of HAX-1, confirmed by co-immunoprecipitation and co-localization. Yeast two-hybrid screen, co-immunoprecipitation, confocal microscopy, deletion mutant analysis Journal of immunology High 9058808
1997 BCR-associated tyrosine kinases Lyn and Syk synergistically phosphorylate HS1 at Tyr-378 and Tyr-397; mutation of these sites to phenylalanine abolishes BCR-induced apoptosis and prevents nuclear translocation of HS1, indicating tyrosine phosphorylation at these sites is required for apoptosis and nuclear targeting. Site-directed mutagenesis, transfection of M1 cells, apoptosis assay, subcellular localization by immunofluorescence The Journal of experimental medicine High 9104825
1999 Tyr-222 is the HS1 residue phosphorylated by Src-family kinases c-Fgr and Lyn (secondary phosphorylation step); stable association of phospho-HS1 with c-Fgr requires prior Syk phosphorylation and c-Fgr autophosphorylation, and is prevented by subsequent Tyr-222 phosphorylation (i.e., once secondary phosphorylation is complete, the complex dissociates). The proline-rich region flanked by the Syk and Src target tyrosines functions as a sequential phosphorylation domain. Mass spectrometry peptide identification, in vitro kinase assay, co-immunoprecipitation, kinetic analysis with truncated HS1 forms The Journal of biological chemistry High 10066823
1999 HS1 interacts with HS1BP3 via the HS1 SH3 domain; overexpression of a dominant-negative HS1BP3 in T cell lines reduces IL-2 production, suggesting HS1BP3 mediates HS1 signaling in lymphocyte activation. Yeast two-hybrid, co-immunoprecipitation, overexpression/dominant-negative in T cell lines, IL-2 assay International immunology Medium 10590261
2000 HS1 interacts directly with the Lyn SH3 domain via its proline-rich region; truncated HS1 bearing the Lyn-binding domain suppresses erythropoietin-induced proliferation and differentiation of erythroid cells, reduces Lyn and GATA-1 levels, and EPO stimulation triggers endosome-mediated degradation of HS1. Yeast two-hybrid, transfection of truncated HS1 in erythroleukemic cells, colony assay, morphological analysis The Journal of biological chemistry Medium 10713104
2000 CK2 phosphorylates HS1 at Ser/Thr residues (mainly threonyl) in the N-terminal and central regions; this Ser/Thr phosphorylation potentiates subsequent Tyr phosphorylation of HS1 by Syk/Src kinases. In vitro kinase assay with CK2, okadaic acid treatment of platelets, CK2 inhibitor treatment, deleted HS1 forms European journal of biochemistry Medium 10806407
2001 Caspase-3 cleaves HS1 in a caspase-dependent manner during apoptosis; HS1 has two clusters of caspase cleavage sites—one in the actin-binding domain and one near the SH3 domain—and CK2-mediated phosphorylation of HS1 renders it resistant to caspase-3 cleavage. In vitro caspase cleavage assay, cell apoptosis assay with CK2 inhibitor TBB, anti-Fas and etoposide treatment Biochemical and biophysical research communications / The Biochemical journal High 11689006 11988074
2003 HS1 directly binds purified Arp2/3 complex (Kd ~880 nM) and F-actin (Kd ~400 nM), promotes Arp2/3-mediated actin polymerization and branched filament formation in vitro, and co-localizes with Arp2/3 complex in cells. Recombinant protein binding assay, pyrene actin polymerization assay, immunofluorescence co-localization The Biochemical journal High 12534372
2005 The coiled-coil region of HS1 is required for binding to F-actin and for Arp2/3 complex activation; the repeat domain is needed for Arp2/3 binding; these two domains act synergistically. A peptide containing only the coiled-coil sequence is sufficient for F-actin binding. Wild-type HS1 co-localizes with cortical F-actin at the cell leading edge, while coiled-coil or repeat deletion mutants diffuse in the cytoplasm. Deletion mutagenesis, in vitro F-actin cosedimentation, Arp2/3 actin nucleation assay, GFP fusion live-cell imaging, co-immunoprecipitation The Journal of biological chemistry High 16157603
2005 Thrombin stimulation of human platelets induces Syk-mediated primary phosphorylation of HS1 at Tyr397, enabling HS1 docking to the Lyn SH2 domain; Lyn then catalyzes secondary phosphorylation at Tyr222. This phosphorylation-dependent translocation of HS1 to the plasma membrane is required for cytoskeletal rearrangement in platelets. Pharmacological inhibitors (PP2, SU6656, piceatannol), phosphosite-specific antibodies, co-immunoprecipitation, immunofluorescence microscopy The Journal of biological chemistry High 15795233
2006 HS1-deficient T cells fail to accumulate F-actin at the immune synapse (IS) and form disordered, unstable actin-rich structures upon TCR ligation; Ca2+ influx and IL-2 gene transcription are defective. Tyrosine phosphorylation of HS1 is required for its targeting to the IS, for actin dynamics regulation, and for stable recruitment of Vav1 to the IS. HS1 phosphorylation links it to Lck, PLCγ1, and Vav1. HS1 KO T cells, live-cell actin imaging at IS, Ca2+ flux assay, IL-2 promoter reporter, phosphotyrosine mutant re-expression, co-immunoprecipitation Immunity High 16782030
2007 HS1 is phosphorylated downstream of glycoprotein VI (GPVI) in platelets by Src-family kinases; HS1 associates with Syk and PI3-kinases by co-immunoprecipitation. HS1-null mice show increased bleeding times, delayed thrombosis, impaired platelet aggregation and secretion downstream of GPVI and PAR-4, and reduced Akt phosphorylation. HS1-null mouse platelet assays (aggregation, secretion, bleeding time, FeCl3 thrombosis), co-immunoprecipitation, kinase inhibition Blood High 17579181
2008 In natural killer cells, HS1 is required for lytic synapse formation, cytolysis, adhesion, chemotaxis, and actin assembly. Tyr397 phosphorylation is specifically required for adhesion to ICAM-1 and cytolysis (integrin signaling and integrin/adaptor/actin recruitment to lytic synapse), while Tyr378 phosphorylation is required for chemotaxis—demonstrating distinct, separable functions for the two phosphotyrosines. HS1 knockdown in NK cells, phosphotyrosine-specific mutant re-expression, cytolysis assay, adhesion assay, chemotaxis assay, actin imaging Nature immunology High 18587398
2010 HS1 controls cytoskeletal remodeling required for CLL B-cell migration, adhesion, and homing; HS1-silenced CLL cells show impaired in vitro migration, abnormal adhesion, and increased homotypic aggregation. In vivo, HS1-silenced CLL cells show decreased organ infiltration except bone marrow; Eμ-TCL1/HS1-KO mice show earlier disease onset and reduced survival. HS1 siRNA in MEC1 CLL cells, HS1-/- mouse B cells, in vitro migration/adhesion assays, in vivo xenograft in Rag2-/-γc-/- mice, Eμ-TCL1 x HS1-KO survival analysis Blood High 20530793
2011 HS1 is required for receptor-mediated endocytosis (but not phagocytosis or macropinocytosis) in dendritic cells; HS1-/- DCs show defective antigen uptake and cross-presentation of protein antigen but normal peptide presentation. HS1 interacts with dynamin-2, and its loss decreases endocytic invaginations. HS1-/- DC functional assays, Ag uptake (endocytosis, phagocytosis, macropinocytosis), OVA protein/peptide presentation to T cells, co-immunoprecipitation with dynamin-2, EM analysis of endocytic intermediates Journal of immunology High 22031761
2012 HCLS1 is phosphorylated in response to G-CSF stimulation, binds the transcription factor LEF-1, and transports LEF-1 into the nucleus, inducing LEF-1 autoregulation. In HAX1-mutant severe congenital neutropenia patients, G-CSF-triggered HCLS1 phosphorylation is profoundly defective, leading to reduced LEF-1 expression and neutropenia. HCLS1-deficient mice are neutropenic. Co-immunoprecipitation (HCLS1–LEF-1), nuclear transport assay, G-CSF stimulation and phosphorylation analysis in human myeloid cells and patient samples, HCLS1-KO mouse analysis Nature medicine High 23001182
2012 In neutrophils, HS1 localizes to the leading edge, is phosphorylated in response to fMLP, and is required for chemoattractant-induced Rac GTPase activation, Vav1 phosphorylation, and chemotaxis. Tyr222 (along with Tyr378 and Tyr397) phosphorylation regulates HS1–Arp2/3 interaction and is required for directional migration rescue. HS1 knockdown in PLB-985 neutrophil-like cells, live imaging in microchannels, Rac GTPase activation assay, Vav1 phosphorylation, phosphomutant re-expression, Arp2/3 co-immunoprecipitation The Journal of biological chemistry High 22679023
2013 LYN kinase phosphorylates HS1 at Tyr397 in a subset of CLL patients with activated LYN; this LYN/HS1 axis drives increased cytoskeletal functionality (migration, adhesion, F-actin polymerization), activates VAV1 and ERK, and promotes CLL cell survival. Dasatinib inhibition of LYN abrogates HS1-Y397 phosphorylation and reduces cytoskeletal activity and BCR signaling. Phosphosite-specific antibodies, dasatinib kinase inhibition, siRNA knockdown, migration/adhesion/F-actin assays, EμTCL1 transplantable mouse model Blood High 23325840
2014 SDF1α (CXCL12)/CXCR4 signaling induces rapid Tyr378 phosphorylation of HS1, enabling it to associate with the Nck SH2 domain; this HS1-Nck complex promotes actin polymerization and T cell migration. Knockdown of either HS1 or Nck impairs SDF1α-induced actin polymerization and T-cell migration. Co-immunoprecipitation, siRNA knockdown of HS1 and Nck, actin polymerization assay, T cell migration assay, chemokine stimulation European journal of immunology Medium 25359136
2017 Wnt5a induces ROR1 to complex with HS1 via ROR1's proline-rich domain (PRD; specifically Pro841); this complex recruits ARHGEF1, activates RhoA, phosphorylates HS1 on Tyr, and enhances CLL cell F-actin polymerization and chemokine-directed migration. ROR1-P841A mutant cannot recruit HS1 or ARHGEF1 and fails to enhance motility. Co-immunoprecipitation, ROR1 domain truncation and point mutants, RhoA activation assay, F-actin assay, CLL cell migration assay, anti-ROR1 mAb (cirmtuzumab) inhibition Leukemia High 28465529
2017 HS1 deficiency reduces neutrophil adhesion and transmigration in vivo (cremaster venule intravital microscopy) and impairs CXCL1-induced activation of Rac1 and Rap1 GTPases (with Rac1 acting upstream of Rap1), which are required for LFA-1-mediated neutrophil adhesion and extravasation. Intravital microscopy, HS1-KO and Rac1-KO neutrophils, GTPase activation assays, adhesion under flow, chemotaxis assay Journal of leukocyte biology High 28122813
2011 The HS1 SH3 domain binds lysine-rich class II PxxPxK proline motifs derived from HPK1; additional basic residues C-terminal to the PxxPxK core are required for binding. The SH3 domain alone and full-length HS1 bind the same peptide with similar affinity, indicating the SH3 domain governs this interaction. GST-SH3 fusion protein expression, circular dichroism-based non-immobilized ligand interaction assay, peptide mutagenesis, in silico modeling Amino acids Medium 21287358
2019 Human cytomegalovirus latency upregulates HCLS1 expression in CD14+ monocytes in a US28-dependent manner; elevated HCLS1 stabilizes actin structure, increases cell motility, and enhances transendothelial migration of latently infected cells. Proteomics of latently infected monocytes, US28 mutant virus, actin staining, transendothelial migration assay, HCLS1 knockdown iScience Medium 31569051
2004 A four-amino-acid (EPEP) insertion polymorphism in HS1 at position 366-367 (in the proline-rich region) confers 100-fold greater sensitivity to BCR-mediated apoptosis in transfected WEHI-231 cells compared to wild-type HS1, indicating the proline-rich region modulates the strength of BCR apoptotic signaling. Transfection of HS1 variants into WEHI-231 cells, BCR crosslinking apoptosis assay, patient genomic analysis Arthritis and rheumatism Medium 15022330

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases. Journal of immunology (Baltimore, Md. : 1950) 215 9058808
2002 Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. The Biochemical journal 193 11988074
2006 HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse. Immunity 169 16782030
1993 Identification of HS1 protein as a major substrate of protein-tyrosine kinase(s) upon B-cell antigen receptor-mediated signaling. Proceedings of the National Academy of Sciences of the United States of America 164 7682714
2010 Genomic deletion of the whole IgH 3' regulatory region (hs3a, hs1,2, hs3b, and hs4) dramatically affects class switch recombination and Ig secretion to all isotypes. Blood 121 20538806
2007 HS1-associated protein X-1 regulates carcinoma cell migration and invasion via clathrin-mediated endocytosis of integrin alphavbeta6. Cancer research 117 17545607
1995 Antigen-receptor induced clonal expansion and deletion of lymphocytes are impaired in mice lacking HS1 protein, a substrate of the antigen-receptor-coupled tyrosine kinases. The EMBO journal 117 7641686
1997 Role of tyrosine phosphorylation of HS1 in B cell antigen receptor-mediated apoptosis. The Journal of experimental medicine 91 9104825
2006 Identification and functional characterization of hCLS1, a human cardiolipin synthase localized in mitochondria. The Biochemical journal 79 16716149
2000 Interaction of Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) with HS1-associated protein X-1: implication of cytoplasmic function of EBNA-LP. Journal of virology 79 11024139
2012 Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis. Nature medicine 72 23001182
2010 HS1 has a central role in the trafficking and homing of leukemic B cells. Blood 72 20530793
2003 Haematopoietic lineage cell-specific protein 1 (HS1) promotes actin-related protein (Arp) 2/3 complex-mediated actin polymerization. The Biochemical journal 68 12534372
2005 HS1 protein is differentially expressed in chronic lymphocytic leukemia patient subsets with good or poor prognoses. The Journal of clinical investigation 62 15931393
2001 Targeted deletion of 5'HS1 and 5'HS4 of the beta-globin locus control region reveals additive activity of the DNaseI hypersensitive sites. Blood 62 11567985
1995 Restoration of surface IgM-mediated apoptosis in an anti-IgM-resistant variant of WEHI-231 lymphoma cells by HS1, a protein-tyrosine kinase substrate. Proceedings of the National Academy of Sciences of the United States of America 61 7638185
1995 Molecular subtyping scheme for serotypes HS1 and HS4 of Campylobacter jejuni. Journal of clinical microbiology 60 7540628
2005 A variant in the HS1-BP3 gene is associated with familial essential tremor. Neurology 57 15699368
2006 Purification and characterization of Heteroscorpine-1 (HS-1) toxin from Heterometrus laoticus scorpion venom. Toxicon : official journal of the International Society on Toxinology 56 17056081
2006 Cloning and characterization of a cDNA encoding human cardiolipin synthase (hCLS1). Journal of lipid research 52 16547353
2017 Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells. Leukemia 51 28465529
1997 Virtually identical enhancers containing a segment of homology to murine 3'IgH-E(hs1,2) lie downstream of human Ig C alpha 1 and C alpha 2 genes. Journal of immunology (Baltimore, Md. : 1950) 51 9233627
2006 Flanking HS-62.5 and 3' HS1, and regions upstream of the LCR, are not required for beta-globin transcription. Blood 50 16645164
2013 Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia. Blood 48 23325840
1981 Isolation and characterization of spontaneously occurring TOL plasmid mutants of Pseudomonas putida HS1. Journal of bacteriology 48 7240090
2005 Comparative genome analysis of cortactin and HS1: the significance of the F-actin binding repeat domain. BMC genomics 47 15710041
2008 Differently phosphorylated forms of the cortactin homolog HS1 mediate distinct functions in natural killer cells. Nature immunology 46 18587398
2007 Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in beta-thalassemic mice. Blood 46 17921347
1996 SH2 domains mediate the sequential phosphorylation of HS1 protein by p72syk and Src-related protein tyrosine kinases. Biochemistry 45 8611520
2003 Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) forms complexes with a cellular anti-apoptosis protein Bcl-2 or its EBV counterpart BHRF1 through HS1-associated protein X-1. Microbiology and immunology 43 12636258
1997 Identification of a homolog of the C alpha 3'/hs3 enhancer and of an allelic variant of the 3'IgH/hs1,2 enhancer downstream of the human immunoglobulin alpha 1 gene. European journal of immunology 43 9394827
1987 Ultrastructural, immunocytochemical, and cytogenetic characterization of a human epithelioid sarcoma cell line (RM-HS1). Journal of the National Cancer Institute 42 2432306
2005 The coiled-coil domain is required for HS1 to bind to F-actin and activate Arp2/3 complex. The Journal of biological chemistry 41 16157603
1999 Molecular features underlying the sequential phosphorylation of HS1 protein and its association with c-Fgr protein-tyrosine kinase. The Journal of biological chemistry 40 10066823
2000 HS1 interacts with Lyn and is critical for erythropoietin-induced differentiation of erythroid cells. The Journal of biological chemistry 39 10713104
2004 Increased frequency of the immunoglobulin enhancer HS1,2 allele 2 in coeliac disease. Scandinavian journal of gastroenterology 37 15545166
2001 HS1,2 enhancer regulation of germline epsilon and gamma2b promoters in murine B lymphocytes: evidence for specific promoter-enhancer interactions. Journal of immunology (Baltimore, Md. : 1950) 36 11544313
2001 High-resolution mapping of YACs and the single-copy gene Hs1(pro-1) on Beta vulgaris chromosomes by multi-colour fluorescence in situ hybridization. Plant molecular biology 35 11247602
2001 Caspase-mediated cleavage of actin-binding and SH3-domain-containing proteins cortactin, HS1, and HIP-55 during apoptosis. Biochemical and biophysical research communications 35 11689006
1996 Concerted repression of an immunoglobulin heavy-chain enhancer, 3' alpha E(hs1,2). Proceedings of the National Academy of Sciences of the United States of America 35 8633077
1996 Distinct binding patterns of HS1 to the Src SH2 and SH3 domains reflect possible mechanisms of recruitment and activation of downstream molecules. International immunology 35 8943564
1997 Rapid tyrosine phosphorylation of HS1 in the response of mouse lymphoma L5178Y-R cells to photodynamic treatment sensitized by the phthalocyanine Pc 4. Photochemistry and photobiology 33 9230709
2012 Enhancers located in heavy chain regulatory region (hs3a, hs1,2, hs3b, and hs4) are dispensable for diversity of VDJ recombination. The Journal of biological chemistry 32 22270371
2008 Existence of multiple isoforms of HS1-associated protein X-1 in murine and human tissues. Journal of molecular biology 32 18472110
2004 Evolution of human IgH3'EC duplicated structures: both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites. Gene 32 15716094
1998 Full activity from human beta-globin locus control region transgenes requires 5'HS1, distal beta-globin promoter, and 3' beta-globin sequences. Blood 32 9657768
2012 The actin regulatory protein HS1 interacts with Arp2/3 and mediates efficient neutrophil chemotaxis. The Journal of biological chemistry 31 22679023
2018 Hematopoietic cell-specific lyn substrate (HCLS1 or HS1): A versatile actin-binding protein in leukocytes. Journal of leukocyte biology 30 30537294
2012 HS1, a Lyn kinase substrate, is abnormally expressed in B-chronic lymphocytic leukemia and correlates with response to fludarabine-based regimen. PloS one 30 22768161
2005 Thrombin-induced tyrosine phosphorylation of HS1 in human platelets is sequentially catalyzed by Syk and Lyn tyrosine kinases and associated with the cellular migration of the protein. The Journal of biological chemistry 30 15795233
1995 Molecular cloning and characterization of mouse HS1. Biochemical and biophysical research communications 30 7535527
2016 Kostmann's Disease and HCLS1-Associated Protein X-1 (HAX1). Journal of clinical immunology 29 27943080
2011 Position and sequence conservation in Amniota of polymorphic enhancer HS1.2 within the palindrome of IgH 3'Regulatory Region. BMC evolutionary biology 27 21406099
2009 N(alpha)-tosyl-L-phenylalanine chloromethyl ketone induces caspase-dependent apoptosis in transformed human B cell lines with transcriptional down-regulation of anti-apoptotic HS1-associated protein X-1. The Journal of biological chemistry 27 19679660
1999 Isolation and characterization of a novel HS1 SH3 domain binding protein, HS1BP3. International immunology 26 10590261
2004 The HoxC4 homeodomain protein mediates activation of the immunoglobulin heavy chain 3' hs1,2 enhancer in human B cells. Relevance to class switch DNA recombination. The Journal of biological chemistry 25 15252056
2012 Polymorphisms of the IgH enhancer HS1.2 and risk of systemic lupus erythematosus. Annals of the rheumatic diseases 24 22294636
2007 Polymorphism of immunoglobulin enhancer element HS1,2A: allele *2 associates with systemic sclerosis. Comparison with HLA-DR and DQ allele frequency. Annals of the rheumatic diseases 24 17392350
2007 Hematopoietic lineage cell specific protein 1 (HS1) is a functionally important signaling molecule in platelet activation. Blood 24 17579181
1997 Evaluation of the role of the 3'alpha heavy chain enhancer [3'alpha E(hs1,2)] in Vh gene somatic hypermutation. Molecular immunology 24 9293770
1994 A novel deletion of approximately 27 kb including the beta-globin gene and the locus control region 3'HS-1 regulatory sequence: beta zero-thalassemia or hereditary persistence of fetal hemoglobin? Blood 24 7507736
1995 Hierarchical phosphorylation of a 50-kDa protein by protein tyrosine kinases TPK-IIB and C-Fgr, and its identification as HS1 hematopoietic-lineage cell-specific protein. European journal of biochemistry 23 7744027
2008 Allele *2 of the HS1,2A enhancer of the Ig regulatory region associates with rheumatoid arthritis. Annals of the rheumatic diseases 22 18952640
2006 HS1-BP3 gene variant is common in familial essential tremor. Movement disorders : official journal of the Movement Disorder Society 22 16211613
1999 Ig heavy chain expression and class switching in vitro from an allele lacking the 3' enhancers DNase I-hypersensitive hs3A and hs1,2. Journal of immunology (Baltimore, Md. : 1950) 22 10072526
2007 Studies on the actin-binding protein HS1 in platelets. BMC cell biology 21 17996076
2009 Allele *1 of HS1.2 enhancer associates with selective IgA deficiency and IgM concentration. Journal of immunology (Baltimore, Md. : 1950) 20 20007591
1999 Cutting edge: Ig heavy chain 3' HS1-4 directs correct spatial position-independent expression of a linked transgene to B lineage cells. Journal of immunology (Baltimore, Md. : 1950) 20 10528158
2006 HS1-associated protein X-1 interacts with membrane-bound IgE: impact on receptor-mediated internalization. Journal of immunology (Baltimore, Md. : 1950) 19 16818771
2019 Human Cytomegalovirus Upregulates Expression of HCLS1 Resulting in Increased Cell Motility and Transendothelial Migration during Latency. iScience 18 31569051
2017 HS1 deficiency impairs neutrophil recruitment in vivo and activation of the small GTPases Rac1 and Rap1. Journal of leukocyte biology 18 28122813
2015 Role of cortactin homolog HS1 in transendothelial migration of natural killer cells. PloS one 18 25723543
1998 Uncoupling activation-dependent HS1 phosphorylation from nuclear factor of activated T cells transcriptional activation in Jurkat T cells: differential signaling through CD3 and the costimulatory receptors CD2 and CD28. Journal of immunology (Baltimore, Md. : 1950) 18 9794375
2013 Suppressive effect of CORM-2 on LPS-induced platelet activation by glycoprotein mediated HS1 phosphorylation interference. PloS one 17 24376647
2011 The actin regulatory protein HS1 is required for antigen uptake and presentation by dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 17 22031761
2000 Ser/Thr phosphorylation of hematopoietic specific protein 1 (HS1): implication of protein kinase CK2. European journal of biochemistry 17 10806407
1996 A comparative study of the phosphotyrosyl phosphatase specificity of protein phosphatase type 2A and phosphotyrosyl phosphatase type 1B using phosphopeptides and the phosphoproteins p50/HS1, c-Fgr and Lyn. European journal of biochemistry 17 8612628
2021 3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression. eLife 15 34585664
2019 Improved growth performance due to hypertrophied intestinal absorptive epithelial cells by heat-killed Lactobacillus sakei HS-1 in broiler chickens1. Journal of animal science 15 30788512
2016 The actin binding proteins cortactin and HS1 are dispensable for platelet actin nodule and megakaryocyte podosome formation. Platelets 15 27778524
2014 Streptomyces flavogriseus HS1: isolation and characterization of extracellular proteases and their compatibility with laundry detergents. BioMed research international 15 24804214
2009 Allelic frequencies of 3' Ig heavy chain locus enhancer HS1,2-A associated with Ig levels in patients with schizophrenia. International journal of immunopathology and pharmacology 15 19309558
2022 ΔF659 and F659S substitutions at the HS1 of FKS2 gene, along with E655A and W715L upstream and downstream substitutions, correlate with high ibrexafungerp MICs against Candidaglabrata. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 14 35427779
2010 Traumatic brain injury induces an up-regulation of Hs1-associated protein X-1 (Hax-1) in rat brain cortex. Neurochemical research 14 21136158
2005 Identification of p54(nrb) and the 14-3-3 Protein HS1 as TNF-alpha-inducible genes related to cell cycle control and apoptosis in human arterial endothelial cells. Journal of biochemistry and molecular biology 14 16053712
2004 Association of a four-amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: molecular and functional analysis. Arthritis and rheumatism 14 15022330
2003 Aberrant HS1 molecule in a patient with systemic lupus erythematosus. Genes and immunity 14 12618860
2017 The Arp2/3 complex binding protein HS1 is required for efficient dendritic cell random migration and force generation. Integrative biology : quantitative biosciences from nano to macro 13 28678266
2014 SDF1α-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells. European journal of immunology 13 25359136
2004 The polymorphism of the locus control region lying downstream the human IgH locus is restricted to hs1,2 but not to hs3 and hs4 enhancers. Immunology letters 13 15234538
1994 Tyrosine phosphorylation of MB-1, B29, and HS1 proteins in human B cells following receptor crosslinking. Immunology letters 13 7927516
2009 Molecular analysis of gamma-globin promoters, HS-111 and 3'HS1, in beta-thalassemia intermedia patients associated with high levels of Hb F. Hemoglobin 12 19958188
2013 Feeding strategies for the improved biosynthesis of canthaxanthin from enzymatic hydrolyzed molasses in the fed-batch fermentation of Dietzia natronolimnaea HS-1. Bioresource technology 11 24384310
2012 2,3,7,8-tetrachlorodibenzo-p-dioxin induces transcriptional activity of the human polymorphic hs1,2 enhancer of the 3'Igh regulatory region. Journal of immunology (Baltimore, Md. : 1950) 11 22357631
2011 The SH3 domain of HS1 protein recognizes lysine-rich polyproline motifs. Amino acids 10 21287358
2011 A novel PrP partner HS-1 associated protein X-1 (HAX-1) protected the cultured cells against the challenge of H₂O₂. Journal of molecular neuroscience : MN 10 21301993
2000 The lymphoid-specific cofactor OBF-1 is essential for the expression of a V(H) promoter/HS1,2 enhancer-linked transgene in late B cell development. Molecular immunology 10 11282393
2018 Hematopoietic lineage cell-specific protein 1 (HS1), a hidden player in migration, invasion, and tumor formation, is over-expressed in ovarian carcinoma cells. Oncotarget 9 30220969
2014 The change in Ig regulation from children to adults disconnects the correlation with the 3'RR hs1.2 polymorphism. BMC immunology 9 25391515
1994 Construction of a YAC library from a Beta vulgaris fragment addition and isolation of a major satellite DNA cluster linked to the beet cyst nematode resistance locus Hs1 (pat-1.). TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 9 24177891