Affinage

HIP1R

Huntingtin-interacting protein 1-related protein · UniProt O75146

Length
1068 aa
Mass
119.4 kDa
Annotated
2026-06-10
36 papers in source corpus 21 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HIP1R is a multi-domain endocytic adaptor that physically couples clathrin-coated pits to the actin cytoskeleton and times actin assembly so that it is transient and directional at endocytic sites (PMID:11564758, PMID:14742709). Its central coiled-coil domain forms stable homodimers and binds clathrin light chain through a conserved 22-residue N-terminal sequence, stimulating clathrin cage assembly; light-chain binding in turn drives HIP1R into a compact conformation that suppresses its own actin engagement, making clathrin a negative regulator of the HIP1R–actin interaction (PMID:11889126, PMID:15533940, PMID:18790740). Actin binding is mediated by the C-terminal THATCH/I-LWEQ module, whose five-helix bundle engages F-actin through a conserved surface patch and is held in check by intrasteric occlusion and an oligomerizing C-terminal latch (PMID:16415883, PMID:15581353). HIP1R restrains actin polymerization at coated pits through two further activities: its proline-rich C-terminus binds the cortactin SH3 domain to block actin filament barbed-end elongation, and loss of HIP1R causes coated structures to remain stably and aberrantly associated with dynamin, actin, Arp2/3, and cortactin (PMID:14742709, PMID:17318189). Its membrane-binding ANTH/ENTH domain binds 3-phosphoinositides and ubiquitin, the latter through a domain-specific site that supports ubiquitin-dependent cargo internalization (PMID:14732715, PMID:34821552). Beyond core endocytosis, HIP1R routes receptor cargo to degradative or stabilizing fates—it prolongs growth factor receptor half-life and mediates EGFR endocytosis required for downstream ERK/Akt signaling and dendritic outgrowth (PMID:14732715, PMID:30574069), and it delivers PD-L1 to the lysosome via a lysosomal targeting signal, controlling PD-L1 abundance and tumor-cell susceptibility to T-cell killing (PMID:30397328, PMID:41184620). In gastric parietal cells, HIP1R is required for tubulovesicle formation, normal apical canalicular membrane architecture, and acid secretory dynamics (PMID:18535670). Conserved function is established by the yeast orthologue Sla2, which negatively regulates Arp2/3-dependent actin polymerization via Pan1p and whose actin attachment is similarly governed by clathrin light chain (PMID:17151356, PMID:21849475).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 High

    Established HIP1R as a clathrin-coated-pit component that physically bridges the clathrin coat to F-actin, defining its core role as an endocytic adaptor.

    Evidence Co-IP, live-cell imaging, immunogold EM of unroofed cells, and in vitro clathrin assembly with structural EM

    PMID:11564758

    Open questions at the time
    • Mechanism timing actin assembly to coat maturation not yet resolved
    • Domain responsible for actin coupling not yet mapped
  2. 2001 Medium

    Showed that clathrin function and HIP1R–clathrin interaction are required to organize coated pits relative to the actin cytoskeleton.

    Evidence Inducible clathrin Hub dominant-negative, pharmacological actin/myosin disruption, immunofluorescence

    PMID:11733052

    Open questions at the time
    • Does not define which HIP1R domains mediate cytoskeletal alignment
    • Indirect pharmacological perturbations
  3. 2002 High

    Distinguished HIP1R from HIP1 by demonstrating direct F-actin co-sedimentation, while mapping clathrin-light-chain binding to the shared central helical domain.

    Evidence In vitro F-actin co-sedimentation, clathrin assembly assay, and AP2/clathrin-heavy-chain binding assays

    PMID:11889126

    Open questions at the time
    • Structural basis of actin binding not defined
    • How actin and clathrin binding are coordinated not addressed
  4. 2004 High

    Defined the molecular determinant of HIP1R–clathrin coupling: a conserved light-chain N-terminal sequence whose mutation abolishes binding and assembly stimulation.

    Evidence In vitro binding with site-directed light-chain mutagenesis, clathrin assembly assay, and cellular actin imaging

    PMID:15533940

    Open questions at the time
    • Does not establish how light-chain binding feeds back on actin engagement
    • Cellular consequence shown only by overexpression
  5. 2004 Medium

    Showed HIP1R actin binding through the I/LWEQ module is intrinsically autoregulated by intrasteric occlusion and stabilizes filaments, revealing built-in control over actin attachment.

    Evidence F-actin co-sedimentation with truncation mutants and depolymerization assay

    PMID:15581353

    Open questions at the time
    • Single biochemical method type
    • Physiological trigger relieving occlusion not identified
  6. 2004 Medium

    Connected HIP1R to membrane recognition and receptor fate, showing ENTH-domain phosphoinositide binding and a role in prolonging growth factor receptor half-life.

    Evidence Lipid-binding assay with ENTH deletion mutant and receptor half-life measurement

    PMID:14732715

    Open questions at the time
    • Mechanism linking lipid binding to receptor stabilization unresolved
    • Apoptosis on ENTH deletion not mechanistically explained
  7. 2004 High

    Demonstrated that HIP1R confers transience on the actin–endocytic interaction, with its depletion trapping coated structures in a stable actin/Arp2/3/cortactin-associated state.

    Evidence RNAi knockdown, FRAP, double-RNAi epistasis with cortactin, and EM of unroofed cells

    PMID:14742709

    Open questions at the time
    • Molecular basis of cortactin dependence not yet defined
    • Did not identify the inhibitory biochemical activity
  8. 2006 High

    Provided the high-resolution structural basis of HIP1R actin binding, identifying the THATCH five-helix bundle, its F-actin surface patch, and an oligomerizing latch.

    Evidence 1.9-Å crystal structure with surface-patch mutagenesis and F-actin binding assay

    PMID:16415883

    Open questions at the time
    • Structure of full-length regulated protein not determined
    • How latch oligomerization is triggered in vivo unknown
  9. 2006 High

    Established conservation of HIP1R's negative regulation of endocytic actin polymerization, showing yeast Sla2 directly inhibits the Arp2/3 activator Pan1p.

    Evidence TAP-MS, in vitro Arp2/3 activation assay, domain mapping, and genetic epistasis in yeast

    PMID:17151356

    Open questions at the time
    • Whether mammalian HIP1R inhibits an Eps15/Pan1 orthologue not tested here
    • Coiled-coil mechanism of Pan1 inhibition not structurally defined
  10. 2007 High

    Identified the biochemical mechanism restraining actin growth: HIP1R proline-rich binding to the cortactin SH3 domain blocks barbed-end elongation, coordinating actin with coat dynamics.

    Evidence In vitro SH3-binding and barbed-end elongation assays, siRNA rescue with deletion mutant, and live imaging

    PMID:17318189

    Open questions at the time
    • How barbed-end inhibition is relieved at scission not defined
    • Quantitative contribution versus other inhibitors unknown
  11. 2007 Medium

    Placed Hip1r downstream of epsin for membrane localization and phosphorylation, with developmental consequences for spore formation in Dictyostelium.

    Evidence Null-mutant genetics, phosphorylation and colocalization assays, double-null epistasis, spore viability

    PMID:17971415

    Open questions at the time
    • Kinase phosphorylating Hip1r not identified
    • Relevance to mammalian HIP1R regulation untested
  12. 2008 High

    Resolved the regulatory logic of HIP1R: it homodimerizes via its coiled coil, and clathrin light-chain binding drives a compact conformation that suppresses THATCH actin binding.

    Evidence Biophysics of recombinant coiled coils, in vivo co-IP for oligomerization, and actin binding +/- clathrin light chain

    PMID:18790740

    Open questions at the time
    • Structural model of the compact conformation not determined
    • Cellular timing of the conformational switch not directly observed
  13. 2008 High

    Defined an in vivo physiological role: HIP1R is required for parietal-cell tubulovesicle formation, canalicular membrane integrity, and acid secretion.

    Evidence Hip1r knockout mouse with EM, localization, acid secretion assay, and gastrin double-knockout epistasis

    PMID:18535670

    Open questions at the time
    • Molecular link between endocytic adaptor function and tubulovesicle biogenesis unresolved
    • Cause of parietal-cell apoptosis not defined
  14. 2009 Medium

    Linked HIP1R to apoptotic machinery via interaction with BCL2L10, with ANTH and THATCH domains contributing to binding and a BAK-dependent death pathway.

    Evidence Yeast two-hybrid, co-IP, Far-Western, domain mapping, apoptosis/caspase assays, and BAK/BAX knockdown

    PMID:19255499

    Open questions at the time
    • Physiological relevance of the apoptotic role unclear
    • Death observed largely on ectopic overexpression
  15. 2010 Medium

    Established epsin's ENTH domain as sufficient to restore Hip1r membrane localization and phosphorylation, defining an upstream regulator of Hip1r positioning.

    Evidence Dictyostelium null analysis, ENTH-domain rescue, phosphorylation mobility shift, double-null epistasis

    PMID:20923836

    Open questions at the time
    • Mechanism of ENTH-driven phosphorylation unknown
    • Mammalian conservation of epsin–HIP1R axis untested
  16. 2011 High

    Extended the clathrin-light-chain regulatory mechanism in yeast, showing CLC controls endocytic progression by gating Sla2–actin attachment through the THATCH domain.

    Evidence Synthetic genetic array, F-actin sedimentation with CLC and Sla2, and THATCH-dependent epistasis

    PMID:21849475

    Open questions at the time
    • Direct demonstration in mammalian cells not provided here
    • Timing of CLC release during endocytosis not resolved
  17. 2018 High

    Defined a degradative cargo-targeting function: HIP1R delivers PD-L1 to lysosomes, controlling its abundance and tumor susceptibility to T-cell killing.

    Evidence Reciprocal co-IP, RNAi with PD-L1 flow cytometry, T-cell cytotoxicity co-culture, and PD-LYSO chimeric peptide

    PMID:30397328

    Open questions at the time
    • The lysosomal targeting signal sequence determinant not fully mapped here
    • How PD-L1 is selected as cargo unresolved
  18. 2018 Medium

    Showed HIP1R mediates EGFR endocytosis and downstream ERK/Akt signaling required for dendritic branching, linking its adaptor role to receptor signaling output.

    Evidence siRNA knockdown, EGFR endocytosis assay, ERK/Akt Western blots, dominant-negative co-IP, neuronal morphology

    PMID:30574069

    Open questions at the time
    • Reconciliation with earlier receptor-stabilization role not addressed
    • Direct vs indirect EGFR interaction not fully resolved
  19. 2021 High

    Identified a ubiquitin-binding site within the ANTH domain that supports ubiquitin-dependent cargo internalization, adding cargo recognition to HIP1R's membrane functions.

    Evidence Structural characterization, in vitro µM-affinity Ub binding, and genetic epistasis with a Ub-dependent GPCR reporter in yeast

    PMID:34821552

    Open questions at the time
    • Mammalian ubiquitinated cargo not directly identified
    • Functional only in combination with other Ub-binding proteins
  20. 2022 Low

    Reported a HIP1R–PTEN interaction proposing HIP1R-mediated PTEN endocytosis in thyroid cancer cells.

    Evidence Co-IP, siRNA knockdown, PTEN fractionation/IF, proliferation assay, and flurbiprofen intervention

    PMID:35209947

    Open questions at the time
    • Single co-IP with indirect localization readout, not independently validated
    • Direct endocytosis of PTEN not demonstrated
  21. 2025 Medium

    Mechanistically dissected the PD-L1 degradation route, showing HIP1R is required to shift PD-L1 from recycling endosomes toward late endosomes/lysosomes, exploitable by a small molecule.

    Evidence SPR binding (KD), co-IP, HIP1R siRNA rescue, recycling vs late-endosome colocalization, N-glycosylation analysis, T-cell killing, in vivo tumor model

    PMID:41184620

    Open questions at the time
    • How HIP1R diverts cargo between recycling and degradative routes not defined
    • Generality beyond PD-L1 not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How clathrin-light-chain-driven conformational switching, ubiquitin/lipid cargo recognition, and actin-restraining activities are temporally integrated during a single endocytic event in mammalian cells remains unresolved.
  • No structure of full-length regulated HIP1R in a coat context
  • Mammalian ubiquitinated cargo repertoire undefined
  • Trigger relieving actin inhibition at scission unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0038024 cargo receptor activity 2 GO:0008289 lipid binding 1
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005764 lysosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-168256 Immune System 2 R-HSA-162582 Signal Transduction 1
Partners
BCL2L10CD274CLTBCTTNEGFRPTEN
Complex memberships
clathrin-coated pit

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Hip1R binds to clathrin via its putative central coiled-coil domain; it localizes to clathrin-coated pits in vivo; it promotes clathrin cage assembly in vitro; it is a rod-shaped apparent dimer with globular heads at either end and can assemble clathrin-coated vesicles and F-actin into higher order structures. Co-immunoprecipitation, live-cell fluorescence imaging (Hip1R-YFP / DsRed-clathrin LC), immunogold EM of unroofed cells, in vitro clathrin assembly assay, electron microscopy of protein architecture The Journal of cell biology High 11564758
2004 Hip1R depletion by RNAi causes clathrin-coated structures to become stably associated with dynamin, actin, Arp2/3, and cortactin (rather than transiently), and this stabilization depends on cortactin; demonstrating that Hip1R makes the actin–endocytic machinery interaction transient and functional. FRAP showed dynamic actin filament assembly can occur at CCSs. RNAi knockdown, fluorescence microscopy, FRAP, double RNAi depletion epistasis, EM of unroofed cells Molecular biology of the cell High 14742709
2002 HIP12 (HIP1R) co-sediments with F-actin in vitro (unlike HIP1, which shows no actin interaction). Both HIP1 and HIP1R stimulate clathrin assembly through their central helical domain, and this domain binds directly to clathrin light chain. HIP1R does not bind to AP2 nor to the terminal domain of clathrin heavy chain with high affinity (unlike HIP1). F-actin co-sedimentation assay, in vitro clathrin assembly assay, direct binding assays for clathrin heavy chain terminal domain and AP2 alpha ear The Journal of biological chemistry High 11889126
2004 HIP1R binds clathrin light chains via the conserved 22-amino acid sequence of the light chain N-terminus; HIP1R prefers light chains associated with clathrin heavy chain; mutations in the conserved light-chain sequence that abolish HIP1R binding block HIP1R-stimulated clathrin assembly in vitro; overexpression of the HIP1R-binding light-chain fragment disrupts cellular actin distribution. In vitro binding assays, site-directed mutagenesis of clathrin light chain, in vitro clathrin assembly assay, overexpression in cells with actin imaging The Journal of biological chemistry High 15533940
2007 The C-terminal proline-rich domain of Hip1R binds the SH3 domain of cortactin; this Hip1R–cortactin complex inhibits actin assembly by blocking actin filament barbed-end elongation. Hip1R deleted for the cortactin-binding site cannot fully rescue the abnormal actin structures at endocytic sites caused by Hip1R siRNA. In vivo, maximum recruitment of Hip1R, clathrin, and cortactin to endocytic sites is coincident and all disappear together upon vesicle formation. In vitro binding assay (proline-rich domain / SH3 interaction), actin assembly assay (barbed-end elongation), siRNA rescue with deletion mutant, live-cell fluorescence imaging The EMBO journal High 17318189
2006 The 1.9-Å crystal structure of the HIP1R THATCH domain reveals a unique five-helix bundle; a large sequence-conserved surface patch formed primarily by helices 3 and 4 mediates F-actin binding, as shown by point mutations at seven contiguous patch residues that significantly reduce F-actin binding. The THATCH domain also has a conserved C-terminal latch capable of oligomerizing the core, modulating F-actin engagement. X-ray crystallography (1.9 Å), site-directed mutagenesis of surface-patch residues, F-actin binding assay Nature structural & molecular biology High 16415883
2008 Hip1 and Hip1R coiled-coil domains form stable homodimers in vitro with no propensity to heterodimerize; homodimers are also predominant in vivo. Clathrin light chain binding induces a compact conformation of Hip1R and significantly reduces actin binding by the THATCH domain, establishing clathrin as a negative regulator of Hip1R–actin interactions. Biophysical analysis of recombinant coiled-coil domains (sedimentation, gel filtration), in vivo co-immunoprecipitation for oligomerization, actin binding assay in the presence/absence of clathrin light chain The Journal of biological chemistry High 18790740
2004 Hip1R (Hip12) binds F-actin through its I/LWEQ module, but actin binding is regulated by intrasteric occlusion — a conserved structural element within the module inhibits the primary actin-binding determinants in the native protein. The I/LWEQ module also contains a dimerization motif and stabilizes actin filaments against depolymerization. F-actin co-sedimentation assay with full-length and truncated proteins, actin depolymerization assay Biochemistry Medium 15581353
2004 HIP1R ENTH domain binds 3-phosphoinositides (preferentially phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,5-bisphosphate); deletion of the ENTH domain abolishes lipid binding and induces apoptosis. Full-length HIP1R prolongs the half-life of growth factor receptors after ligand-induced endocytosis. Lipid-binding assay (ENTH domain deletion mutant), receptor half-life measurement by pulse-chase/Western blotting The Journal of biological chemistry Medium 14732715
2001 Expression of the Hub fragment of clathrin heavy chain (dominant-negative) dissociates Hip1R from coated pits, and disrupts the linear alignment of clathrin-coated pits with the actin cytoskeleton; cytochalasin D (actin disassembly) and BDM (myosin inhibition) also disrupt coated-pit alignment, indicating that proper clathrin function and Hip1R–clathrin interaction are required for cytoskeletal organization of coated pits. Inducible expression of clathrin Hub dominant-negative, immunofluorescence microscopy, pharmacological actin disruption Traffic (Copenhagen, Denmark) Medium 11733052
2008 Hip1r is expressed in gastric parietal cells, localizing predominantly with F-actin to canalicular membranes. Hip1r-deficient mice show loss of tubulovesicles and abnormal apical canalicular membranes in parietal cells, altered acid secretory dynamics, and increased parietal cell apoptosis; normalization of proliferation and gland height in double gastrin/Hip1r knockout mice indicates that elevated gastrin drives glandular hypertrophy secondary to Hip1r loss. Hip1r knockout mouse model, electron microscopy, immunofluorescence/localization, acid secretion assay in isolated gastric glands, double knockout epistasis The Journal of clinical investigation High 18535670
2006 Yeast Hip1R homologue Sla2p directly inhibits Pan1p (yeast Eps15-related Arp2/3 activator) Arp2/3 complex activation activity in vitro; the coiled-coil region of Sla2p is required for Pan1p inhibition; a pan1 partial loss-of-function mutation suppresses temperature sensitivity, endocytic defects, and actin phenotypes of sla2 coiled-coil deletion mutants, placing Sla2p upstream of Pan1p in negative regulation of actin polymerization during endocytosis. Tandem affinity purification–mass spectrometry (Pan1p interactors), in vitro Arp2/3 activation assay, domain-deletion mapping, genetic epistasis (double mutants) Molecular biology of the cell High 17151356
2011 In yeast, clathrin light chain (CLC) N-terminus binding to Sla2 (Hip1R orthologue) inhibits Sla2 interaction with F-actin in actin sedimentation assays; CLC N-terminus deletion suppresses endocytic defects of rvs and vrp1 mutants in a manner requiring the Sla2 THATCH actin-binding domain, suggesting that CLC regulates endocytic progression by controlling Sla2–actin attachments. Synthetic genetic array analysis, F-actin sedimentation assay with CLC and Sla2, genetic epistasis with THATCH domain requirement Molecular biology of the cell High 21849475
2018 HIP1R physically interacts with PD-L1 and delivers PD-L1 to the lysosome via a lysosomal targeting signal; depletion of HIP1R in tumor cells causes PD-L1 accumulation and suppresses T cell-mediated cytotoxicity; a chimeric peptide (PD-LYSO) incorporating HIP1R's lysosomal-sorting signal and PD-L1-binding sequence depletes PD-L1. Co-immunoprecipitation (HIP1R–PD-L1), RNAi knockdown with flow cytometry for PD-L1 levels, T cell cytotoxicity co-culture assay, chimeric peptide functional study Nature chemical biology High 30397328
2010 In Dictyostelium, epsin is required for membrane recruitment and phosphorylation of Hip1r; epsin-null cells phenocopy Hip1r-null cells for actin/clathrin dynamics defects; the ENTH domain of epsin is sufficient to restore Hip1r phosphorylation and restricted plasma-membrane localization, establishing epsin as an upstream regulator of Hip1r localization and phosphorylation. Dictyostelium null mutant analysis, fluorescence imaging of Hip1r localization, phosphorylation detection by mobility shift, ENTH domain rescue experiment, epistasis of double-null cells Journal of cell science Medium 20923836
2007 In Dictyostelium, Hip1r is phosphorylated and localizes to plasma membrane puncta that also contain epsin; both phosphorylation and restricted localization require epsin. Hip1r-null cells form fruiting bodies with morphologically defective (round) spores with decreased viability, and double epsin/Hip1r-null spores are identical to Hip1r single-null spores, placing Hip1r downstream of epsin. Null mutant genetics, phosphorylation assay, colocalization imaging, double-null epistasis, spore morphology and viability assay Journal of cell science Medium 17971415
2009 HIP1R interacts with BCL2L10 (Diva/BCL-B) identified by yeast two-hybrid and confirmed by co-immunoprecipitation and Far-Western analysis in 293T cells; both ANTH and THATCH domains of HIP1R contribute to BCL2L10 binding. Ectopic HIP1R expression induces moderate apoptosis with mitochondrial membrane potential loss and caspase-9 activation; BAK (but not BAX) is required for HIP1R-induced cell death; BCL2L10 associates with caspase-9, and this association is augmented by HIP1R overexpression. Yeast two-hybrid, co-immunoprecipitation, Far-Western analysis, domain-deletion mapping, flow cytometry (apoptosis, mitochondrial potential), caspase activation assay, BAK/BAX knockdown Cellular physiology and biochemistry Medium 19255499
2021 The ANTH domain of HIP1R (and CALM and Sla2) binds ubiquitin via a unique C-terminal region within the ANTH domain not found in ENTH domains; structural studies revealed µM-affinity Ub binding. In yeast functional assays, combined loss of Ub-binding by ANTH-domain proteins together with other Ub-binding domains impairs Ub-dependent internalization of a GPCR (Ste2 engineered to rely exclusively on Ub), but not Ub-independent internalization. Structural studies (binding mode characterization), in vitro ubiquitin-binding assay with µM affinity determination, genetic loss-of-function epistasis in yeast with Ub-signal-dependent internalization reporter eLife High 34821552
2018 Knockdown of HIP1R impairs endocytosis of activated EGFR and reduces downstream ERK and Akt activation in hippocampal neurons; a dominant-negative HIP1R fragment (aa 633-822) interacts with EGFR and disrupts HIP1R-EGFR interaction-mediated dendritic outgrowth, establishing HIP1R as a mediator of EGFR endocytosis and downstream signaling required for dendritic branching. siRNA knockdown, EGFR endocytosis assay, Western blotting for ERK/Akt phosphorylation, dominant-negative fragment co-immunoprecipitation with EGFR, neuronal morphology analysis Frontiers in molecular neuroscience Medium 30574069
2022 HIP1R interacts with PTEN in thyroid cancer cells (by co-immunoprecipitation); knockdown of HIP1R reduces intracellular PTEN but upregulates membrane-bound PTEN, suggesting HIP1R mediates PTEN endocytosis. Flurbiprofen disrupts the HIP1R–PTEN interaction and enhances PTEN membrane binding, and its anti-proliferative effect is attenuated by HIP1R or PTEN knockdown. Co-immunoprecipitation (HIP1R–PTEN), siRNA knockdown, PTEN subcellular fractionation/immunofluorescence, cell proliferation assay, pharmacological intervention European journal of medical research Low 35209947
2025 The small molecule MS1-96 directly binds PD-L1 (KD = 2.58 µM) and enhances the interaction between HIP1R and PD-L1, shifting PD-L1 intracellular trafficking away from recycling endosomes toward late endosomes and lysosomes for degradation; HIP1R knockdown abolishes MS1-96-driven PD-L1 degradation, confirming HIP1R is required for this lysosomal trafficking route. MS1-96 also induces abnormal N-glycosylation of PD-L1, destabilizing the protein. Surface plasmon resonance / binding affinity measurement (KD), co-immunoprecipitation, HIP1R siRNA knockdown, subcellular trafficking assays (colocalization with recycling vs. late endosome markers), N-glycosylation analysis, T cell killing assay, in vivo mouse tumor model Acta pharmacologica Sinica Medium 41184620
2024 Sla2 (Hip1R yeast orthologue) has two independent binding sites for clathrin light chain (CLC): one conserved between Fungi and Metazoa (including Hip1R), and a second found only in Fungi. Pan1p competes with CLC for the conserved binding site on Sla2. Cryo-EM structural model of Sla2 actin-binding domains in regulatory context was presented. Cryo-EM structural modeling, molecular biophysics binding assays, AI-assisted interaction prediction confirmed by experimental biophysics, competition assay (Pan1 vs CLC) bioRxiv (preprint)preprint Medium

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. Nature chemical biology 264 30397328
2001 The actin-binding protein Hip1R associates with clathrin during early stages of endocytosis and promotes clathrin assembly in vitro. The Journal of cell biology 202 11564758
2004 RNAi-mediated Hip1R silencing results in stable association between the endocytic machinery and the actin assembly machinery. Molecular biology of the cell 128 14742709
2004 Huntingtin-interacting protein 1 (Hip1) and Hip1-related protein (Hip1R) bind the conserved sequence of clathrin light chains and thereby influence clathrin assembly in vitro and actin distribution in vivo. The Journal of biological chemistry 96 15533940
2002 HIP1 and HIP12 display differential binding to F-actin, AP2, and clathrin. Identification of a novel interaction with clathrin light chain. The Journal of biological chemistry 89 11889126
2007 A Hip1R-cortactin complex negatively regulates actin assembly associated with endocytosis. The EMBO journal 76 17318189
2008 Actin binding by Hip1 (huntingtin-interacting protein 1) and Hip1R (Hip1-related protein) is regulated by clathrin light chain. The Journal of biological chemistry 68 18790740
2006 Structural definition of the F-actin-binding THATCH domain from HIP1R. Nature structural & molecular biology 68 16415883
2004 Intrasteric inhibition mediates the interaction of the I/LWEQ module proteins Talin1, Talin2, Hip1, and Hip12 with actin. Biochemistry 67 15581353
2004 HIP1 and HIP1r stabilize receptor tyrosine kinases and bind 3-phosphoinositides via epsin N-terminal homology domains. The Journal of biological chemistry 59 14732715
2008 Hip1r is expressed in gastric parietal cells and is required for tubulovesicle formation and cell survival in mice. The Journal of clinical investigation 51 18535670
2006 Hip3 interacts with the HIRA proteins Hip1 and Slm9 and is required for transcriptional silencing and accurate chromosome segregation. The Journal of biological chemistry 44 16428807
2001 Clathrin hub expression dissociates the actin-binding protein Hip1R from coated pits and disrupts their alignment with the actin cytoskeleton. Traffic (Copenhagen, Denmark) 43 11733052
1998 Cloning, expression analysis, and chromosomal localization of HIP1R, an isolog of huntingtin interacting protein (HIP1). Journal of human genetics 41 9852681
2000 HIP12 is a non-proapoptotic member of a gene family including HIP1, an interacting protein with huntingtin. Mammalian genome : official journal of the International Mammalian Genome Society 40 11063258
2011 Clathrin light chain directs endocytosis by influencing the binding of the yeast Hip1R homologue, Sla2, to F-actin. Molecular biology of the cell 39 21849475
2006 Negative regulation of yeast Eps15-like Arp2/3 complex activator, Pan1p, by the Hip1R-related protein, Sla2p, during endocytosis. Molecular biology of the cell 38 17151356
2007 Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1. Human molecular genetics 36 17452370
2010 Regulation of Hip1r by epsin controls the temporal and spatial coupling of actin filaments to clathrin-coated pits. Journal of cell science 34 20923836
2010 The Sla2p/HIP1/HIP1R family: similar structure, similar function in endocytosis? Biochemical Society transactions 31 20074057
2013 Reciprocal expression of the endocytic protein HIP1R and its repressor FOXP1 predicts outcome in R-CHOP-treated diffuse large B-cell lymphoma patients. Leukemia 29 23884370
2009 HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-dependent cell death. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 22 19255499
2012 IFNγ contributes to the development of gastric epithelial cell metaplasia in Huntingtin interacting protein 1 related (Hip1r)-deficient mice. Laboratory investigation; a journal of technical methods and pathology 19 22525425
2022 HIP1R and vimentin immunohistochemistry predict 1p/19q status in IDH-mutant glioma. Neuro-oncology 14 35511748
2007 Dictyostelium Hip1r contributes to spore shape and requires epsin for phosphorylation and localization. Journal of cell science 13 17971415
2023 DNA methylation and miR-92a-3p-mediated repression of HIP1R promotes pancreatic cancer progression by activating the PI3K/AKT pathway. Journal of cellular and molecular medicine 12 36811277
2020 HIP1R acts as a tumor suppressor in gastric cancer by promoting cancer cell apoptosis and inhibiting migration and invasion through modulating Akt. Journal of clinical laboratory analysis 12 32548851
2018 Proteomic analysis identifies NPTX1 and HIP1R as potential targets of histone deacetylase-3-mediated neurodegeneration. Experimental biology and medicine (Maywood, N.J.) 12 29486577
2021 ANTH domains within CALM, HIP1R, and Sla2 recognize ubiquitin internalization signals. eLife 11 34821552
2018 Endocytic Adaptor Protein HIP1R Controls Intracellular Trafficking of Epidermal Growth Factor Receptor in Neuronal Dendritic Development. Frontiers in molecular neuroscience 10 30574069
2022 Flurbiprofen inhibits cell proliferation in thyroid cancer through interrupting HIP1R-induced endocytosis of PTEN. European journal of medical research 9 35209947
2020 HIP1R Expression and Its Association with PD-1 Pathway Blockade Response in Refractory Advanced NonSmall Cell Lung Cancer: A Gene Set Enrichment Analysis. Journal of clinical medicine 8 32403421
2025 Evaluating the efficacy of Hip1R, Vimentin, and H3K27me3 as surrogate markers for 1p/19q co-deletion in oligodendrogliomas. Neuro-oncology advances 5 40351829
2011 The HIRA complex subunit Hip3 plays important roles in the silencing of meiosis-specific genes in Schizosaccharomyces pombe. PloS one 4 21559379
2025 MS1-96 induces HIP1R-dependent PD-L1 degradation and promotes antitumor immunity in colorectal cancer. Acta pharmacologica Sinica 1 41184620
2025 Huntingtin-Interacting Protein 1-Related (HIP1R) Regulates Rheumatoid Arthritis Synovial Fibroblast Invasiveness. Cells 0 40214437

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