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Showing STIP1 — STI1 is a alias.

STIP1

Stress-induced-phosphoprotein 1 · UniProt P31948

Length
543 aa
Mass
62.6 kDa
Annotated
2026-06-10
96 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STIP1 (Hop/Sti1) is a modular co-chaperone adaptor that physically bridges the Hsp70 and Hsp90 chaperone machines to coordinate the maturation of client proteins, a role first established genetically in yeast where Sti1 acts at an intermediate step downstream of Hsp70 (Ydj1) and upstream of mature Hsp90-client complexes (PMID:8972212). It engages the two chaperones through distinct tetratricopeptide repeat (TPR) domains: TPR2A is the high-affinity Hsp90-binding site while TPR1 and TPR2B bind Hsp70, and client folding requires Sti1 to bridge both chaperones simultaneously (PMID:16100115, PMID:22227520). Structurally, Sti1/Hop is an elongated, conformationally dynamic protein in which a rigid TPR2A–TPR2B linker orients the two binding sites in opposite directions to permit concurrent Hsp70 and Hsp90 engagement, with Hsp90 binding shifting Hsp70 away from TPR2B (PMID:22227520, PMID:25851214). Functionally, STIP1 acts as a non-competitive inhibitor of the Hsp90 ATPase, binding both N- and C-terminal regions of Hsp90, stabilizing its domains, and preventing the N-terminal dimerization and N–middle domain docking required for ATP hydrolysis (PMID:12525481, PMID:22354036); this restraining activity is itself negatively regulated by inhibitory phosphorylation that reduces chaperone affinity and client activation (PMID:25504578). By restraining Hsp70–Hsp90 complex formation, STIP1 also governs downstream proteostasis outcomes — its loss reduces 20S proteasome capping and proteasome activity yet paradoxically improves aggregation prevention and refolding via a more efficient Hsp70–Hsp90 binary complex (PMID:33239621) — and during proteostatic stress STIP1 independently sequesters misfolded ubiquitinated proteins into cytoplasmic inclusions in a manner separable from its Hsp90 ATPase regulatory function (PMID:39739753). Beyond canonical chaperoning, STIP1 directly binds cellular prion protein (PrPC) through DP1, TPR1, and TPR2A to support neuroprotective signaling and to block amyloid-β oligomer binding (PMID:15670743, PMID:27208175), and it directly engages α-synuclein via its TPR2A domain, facilitating PLK3-mediated S129 phosphorylation and promoting cytotoxic oligomeric species in vivo (PMID:36121476). STIP1 additionally functions as a scaffold in JAK–STAT3 signaling (PMID:10954736), binds actin and stimulates its ATPase to regulate cytoskeletal organization (PMID:32365744), and contributes to mitochondrial precursor import (PMID:27412066).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1989 Medium

    Established STIP1's founding identity as a stress-inducible factor before any chaperone role was known, linking it to the heat shock response.

    Evidence Gene disruption and overexpression with HSP70 promoter reporter in yeast

    PMID:2674681

    Open questions at the time
    • No molecular mechanism for HSP70 promoter trans-activation defined
    • Direct chaperone partners not yet identified
  2. 1997 High

    Placed Sti1 mechanistically within the Hsp70-to-Hsp90 client maturation pathway, defining it as an intermediate co-chaperone rather than an independent factor.

    Evidence Genetic epistasis with hsp90ts mutants and client (GR, v-Src) activity/Co-IP assays in yeast

    PMID:8972212

    Open questions at the time
    • Domain basis for dual chaperone engagement not yet resolved
    • Biochemical effect on Hsp90 enzymatic activity unknown
  3. 2000 Medium

    Identified a chaperone-independent scaffolding role linking STIP1 to JAK–STAT3 signaling, broadening its functional scope.

    Evidence Co-IP, dominant-negative domain overexpression, and STAT3 reporter/translocation assays

    PMID:10954736

    Open questions at the time
    • Whether scaffolding requires chaperone activity not addressed
    • Single lab, no structural mapping of the STAT3-binding region
  4. 2003 High

    Defined the biochemical mechanism of Hsp90 regulation, showing STIP1 non-competitively inhibits the ATPase by blocking N-terminal dimerization.

    Evidence Reconstituted in vitro ATPase assays and binding to truncated Hsp90 constructs

    PMID:12525481

    Open questions at the time
    • High-resolution structure of the inhibitory module not yet available
    • Coupling to client transfer not directly shown
  5. 2005 High

    Assigned division of labor among Sti1 TPR domains, showing TPR1 governs Hsp70 and TPR2A/TPR2B govern Hsp90 regulation independently.

    Evidence Domain-specific mutagenesis with [PSI+] prion and Hsp90-inhibitor functional assays in yeast

    PMID:16100115 PMID:16219779

    Open questions at the time
    • DP2 essential function mechanistically unexplained
    • Redundancy vs specialization of TPR1/TPR2B not fully resolved
  6. 2005 Medium

    Extended STIP1 function to extracellular neuronal signaling by demonstrating direct PrPC interaction driving neuroprotection.

    Evidence Co-IP, inhibitory peptide competition, and SOD/cell survival assays in neuronal cells

    PMID:15670743

    Open questions at the time
    • Binding interface not mapped at residue level
    • Downstream signaling cascade incompletely defined
  7. 2007 High

    Refined the domain model, showing TPR1/TPR2B redundancy for Hsp70 and that TPR2A drives both Hsp90 binding and Sti1 dimerization while DP2 is dispensable for interactions but essential in vivo.

    Evidence Truncation mutagenesis with in vivo Co-IP and in vitro binding; nucleotide-dependence Co-IP with Hsp90 mutants

    PMID:17101799 PMID:17300223

    Open questions at the time
    • In vivo essential role of DP2 still mechanistically unexplained
    • Conformational coupling between domains not yet visualized
  8. 2010 High

    Demonstrated that Sti1 acts in prion propagation/curing through both its Hsp70 and Hsp90 interactions, integrating its dual-chaperone role into amyloid handling.

    Evidence Genetic epistasis, domain mutants, and Hsp90 inhibitor in yeast [PSI+] curing assays

    PMID:20479121

    Open questions at the time
    • Direct action on prion substrate vs chaperone modulation not separated
    • Relevance to mammalian amyloids not tested here
  9. 2012 High

    Provided the structural basis for simultaneous dual-chaperone bridging and the core Hsp90 inhibitory module, unifying earlier domain genetics.

    Evidence Crystal structure of TPR2A–TPR2B, NMR of DP domains, binding and client activation assays; HX-MS and crosslinking-MS of the Hsp90 complex

    PMID:22227520 PMID:22354036

    Open questions at the time
    • Full-length Hop–Hsp70–Hsp90 ternary structure not solved
    • Dynamics of client handoff not captured
  10. 2014 High

    Revealed STIP1 as a conformationally dynamic adaptor whose Hsp70 preference is allosterically reset by Hsp90 binding, and expanded its roles to spatial protein quality control, cytoskeletal regulation, and inhibitory phosphorylation.

    Evidence Single-molecule FRET and NMR; yeast Htt/Rnq1 suppressor and imaging assays; Rnd1 Co-IP with collapse/neurite assays; phospho-mimetic mutagenesis

    PMID:24109600 PMID:24690281 PMID:25504578 PMID:25851214

    Open questions at the time
    • Physiological kinases for inhibitory sites not identified here
    • Mechanistic link between adaptor dynamics and quality-control function unclear
  11. 2016 Medium

    Mapped the PrPC-binding architecture and showed STIP1 blocks amyloid-β oligomer toxicity, while uncovering additional partners in cytoskeleton, nuclear envelope, mitochondrial import, and Wnt signaling.

    Evidence NMR chemical-shift mapping with PrP/AβO assays; actin Co-IP/ATPase and imaging; emerin Co-IP, domain mapping and rescue; Tom20/Tom70 binding and yeast genetics; Axin Co-IP/Wnt reporter

    PMID:27208175 PMID:27412066 PMID:29596884 PMID:30449594 PMID:32365744

    Open questions at the time
    • Whether non-chaperone partners require Hsp70/Hsp90 engagement not resolved
    • Several interactions rest on single-lab Co-IP without reciprocal structural validation
  12. 2017 High

    Quantified calcium-dependent S100A1 engagement of all three TPR domains, defining STIP1 as a calcium-responsive multivalent TPR hub.

    Evidence Isothermal titration calorimetry with isolated TPR domains and calcium-dependence studies

    PMID:28408431

    Open questions at the time
    • Functional consequence of S100A1 binding for chaperone cycle untested
    • Cellular context of the interaction undefined
  13. 2020 High

    Resolved how loss of STIP1 reshapes proteostasis, showing it is required for proteasome capping yet restrains an intrinsically efficient Hsp70–Hsp90 binary complex.

    Evidence Knockout in human cells and yeast plus in vitro reconstitution of chaperone activity and proteasome/refolding assays

    PMID:33239621

    Open questions at the time
    • Mechanism of proteasome capping defect not detailed
    • When the binary complex is advantageous in vivo unclear
  14. 2021 High

    Established direct, TPR2A-specific engagement of disease-associated aggregating proteins, mechanistically linking STIP1 to synucleinopathy and TDP-43 proteinopathy.

    Evidence Co-IP, NMR mapping, in vitro PLK3 kinase assay and STI1-altered mouse models for α-synuclein; Co-IP and aggregation/toxicity assays for TDP-43

    PMID:33908654 PMID:36121476

    Open questions at the time
    • Whether STIP1 promotes or detoxifies aggregates context-dependent and not fully reconciled
    • TDP-43 binding interface not mapped
  15. 2023 Medium

    Linked STIP1-directed Hsp70-to-Hsp90 client handoff to substrate stabilization in disease-relevant contexts and to oncogenic Wnt signaling.

    Evidence Co-IP, gain/loss-of-function and Hsp90 inhibitor with Cx43 ubiquitination in cardiomyocytes; lncRNA pulldown/Co-IP with β-catenin assays

    PMID:37187948 PMID:37806517

    Open questions at the time
    • LINC01226-driven complex disassembly evidence is indirect
    • Generality across substrates not established
  16. 2025 Medium

    Sharpened the mechanistic picture of STIP1 in mitochondrial import buffering, α-synuclein oligomer toxicity, and a metabolic AHCY/LDHA axis driving tumorigenesis.

    Evidence Photo-crosslinking and reconstitution for MTS-driven import (preprint); NMR/aggregation/cytotoxicity for α-synuclein (preprint); Co-IP, glycolysis/methylation assays and mouse KO for AHCY/LDHA

    PMID:41163796 PMID:bio_10.1101_2025.01.18.633710 PMID:bio_10.1101_2025.03.26.645247

    Open questions at the time
    • Two findings are preprints awaiting peer review
    • AHCY/LDHA metabolic pathway rests on a single low-confidence study with limited reconstitution

Open questions

Synthesis pass · forward-looking unresolved questions
  • How STIP1's many non-canonical activities (cytoskeletal, signaling, metabolic, mitochondrial) mechanistically relate to its core Hsp70/Hsp90 bridging function remains unresolved.
  • No unifying model distinguishing chaperone-dependent from chaperone-independent functions
  • Physiological kinases regulating inhibitory phosphorylation in vivo not defined
  • Full-length structure of the Hop–Hsp70–Hsp90 client complex not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 3 GO:0005576 extracellular region 2 GO:0005634 nucleus 1
Partners
ACTBHSP70HSP90JAK2PRNPS100A1SNCASTAT3
Complex memberships
Hsp70-Hop-Hsp90 chaperone complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 STI1 (yeast ortholog of STIP1) was identified as a stress-inducible gene encoding a ~66 kDa protein; disruption caused impaired growth at high and low temperatures, and overexpression trans-activated the SSA4 (HSP70) promoter, indicating a role in mediating the heat shock response. Gene disruption, overexpression with reporter gene fusion, two-dimensional gel electrophoresis Molecular and cellular biology Medium 2674681
1997 Yeast Sti1 acts as a general co-chaperone at an intermediate step in the Hsp90-dependent maturation of client proteins (glucocorticoid receptor, v-Src); deletion of STI1 reduces GR and v-Src activity in vivo and increases GR-Ydj1 complexes, placing Sti1 downstream of Hsp70 (Ydj1) and upstream of mature Hsp90-client complexes. Genetic epistasis (sti1Δ combined with hsp90ts mutations, GR/v-Src activity assays), co-immunoprecipitation of client complexes in yeast Molecular and cellular biology High 8972212
2000 Human STIP1 (StIP1) preferentially associates with unphosphorylated (inactive) Stat3 and also binds members of the Janus kinase (JAK) family; overexpression of the Stat3-binding domain of STIP1 blocks Stat3 activation, nuclear translocation, and Stat3-dependent transcription, suggesting STIP1 acts as a scaffold promoting JAK–Stat3 interaction. Co-immunoprecipitation, overexpression dominant-negative domain, reporter gene assay, nuclear translocation assay Proceedings of the National Academy of Sciences of the United States of America Medium 10954736
2003 Sti1 is a non-competitive inhibitor of the Hsp90 ATPase; it binds both the N- and C-terminal domains of Hsp90 and prevents the N-terminal dimerization reaction required for efficient ATP hydrolysis, with the first 24 amino acids of Hsp90 being important for this interaction. In vitro ATPase assay, binding analysis with truncated Hsp90 constructs, kinetic inhibition analysis The Journal of biological chemistry High 12525481
2005 Sti1p regulates Hsp70 and Hsp90 independently via distinct TPR domains: TPR1 mutations impair Hsp70 regulation (without affecting Hsp90), while TPR2A/TPR2B mutations impair Hsp90 regulation (without affecting Hsp70); Hsp90 is implicated as a TPR2B ligand; client folding requires Sti1p to bridge both chaperones simultaneously. Site-directed mutagenesis of TPR domains, yeast [PSI+] prion assay for Hsp70 activity, Hsp90-inhibitor assay for Hsp90 activity, client folding assays The Journal of biological chemistry High 16100115
2005 STIP1/STI1 interacts with cellular prion protein (PrPC) via immunoprecipitation; the OR and N-terminal hydrophobic region of PrPC are required for PrPC-STI1-mediated activation of superoxide dismutase (SOD) activity and cell survival signaling. Co-immunoprecipitation, inhibitory peptide competition assays, SOD activity assay in PrP-null and PrP-expressing neuronal cells Biochemical and biophysical research communications Medium 15670743
2005 In yeast, mutations in Sti1 DP2 domain completely disrupt Sti1 function in vivo, while TPR1 and TPR2B have redundant roles in Hsp70 binding; a single amino acid alteration in TPR2A disrupts Hsp90 interaction but does not significantly affect function alone. Site-directed mutagenesis, genetic screen, co-immunoprecipitation in yeast Genetics Medium 16219779
2006 Wild-type Hsp90 binds Sti1 in a nucleotide-independent manner in yeast cell extracts, while Sba1 and Cpr6 interact with Hsp90 specifically in the presence of the non-hydrolyzable ATP analog AMP-PNP; Hsp90 mutations altering ATP binding reduce Sti1 interaction in the presence of nucleotide. Co-immunoprecipitation from yeast extracts with wild-type and mutant Hsp90 forms, AMP-PNP competition Molecular and cellular biology Medium 17101799
2007 Both TPR1 and TPR2B of Sti1 contribute redundantly to Hsp70 binding in vivo; TPR2A is required for Hsp90 interaction but requires TPR2B for full Hsp90 binding in isolation; TPR2A is sufficient for Sti1 dimerization; the DP2 domain is essential for in vivo function but dispensable for Hsp70/Hsp90 interaction or dimerization; Sti1 mutants with reduced Hsp70 interaction show reduced recovery of Hsp70 in Hsp90 complexes. Truncation mutagenesis, in vivo co-immunoprecipitation, in vitro binding assays with purified proteins The Biochemical journal High 17300223
2007 Extracellular/secreted STI1 induces proliferation of human glioblastoma cells (A172) via MAPK (ERK) and PI3K signaling pathways, and this effect involves cellular prion protein (PrPC). Thymidine incorporation assay, pathway inhibitor experiments, extracellular STI1 application Glia Low 17886292
2009 Interaction of PrPC with hop/STI1 induces loss of PrP helical structures (perturbation of PrP helix 143–153) and a C-terminal compaction of hop/STI1, as revealed by CD, fluorescence spectroscopy, and SAXS; free murine hop/STI1 is monomeric by both SAXS and size-exclusion chromatography. Circular dichroism (CD), fluorescence spectroscopy, small angle X-ray scattering (SAXS), size-exclusion chromatography FASEB journal Medium 19703931
2010 Deletion of STI1 in yeast both suppresses Ssa1-21 (Hsp70 mutant)-mediated impairment of [PSI+] and blocks Hsp104-mediated curing of [PSI+] prions; Sti1 variants defective in Hsp70 or Hsp90 interaction cure less efficiently, and Hsp90 inhibitor abolishes curing, demonstrating Sti1 acts in prion curing through both Hsp70 and Hsp90 interactions. Genetic epistasis, STI1 deletion, domain-specific mutations, Hsp90 inhibitor treatment, prion-curing assays in yeast Molecular and cellular biology High 20479121
2012 Sti1/Hop has a modular architecture: TPR2A is the high-affinity Hsp90-binding site; TPR1 and TPR2B bind Hsp70 with moderate affinity; DP1 and DP2 have homologous α-helical folds (determined by NMR); the TPR2A–TPR2B segment is the core Hsp90 inhibitory module; TPR2A and TPR2B are connected by a rigid linker orienting their binding sites in opposite directions, allowing simultaneous binding of TPR2A to Hsp90 C-terminal domain and TPR2B to Hsp70; DP2 is important for client activation in vivo. NMR structure determination of DP domains, crystal structure of TPR2A–TPR2B segment, in vitro binding assays, in vivo client activation assays The EMBO journal High 22227520
2012 Sti1 stabilizes multiple regions in all three domains of Hsp90 and slows dimer dissociation; it inhibits Hsp90 ATPase by preventing N-terminal dimerization and docking of the N-terminal with the middle domain; crosslinking-MS identified Sti1 segments in close proximity to the Hsp90 N-terminal domain; the linker length between Hsp90 C-terminal dimerization domain and MEEVD motif is important for Sti1 association rates. Hydrogen exchange mass spectrometry (HX-MS), crosslinking mass spectrometry, mutant Hsp90 analysis The EMBO journal High 22354036
2013 Sti1 modulates spatial quality control of amyloid-like proteins (Htt103Q, Rnq1) in yeast cytosol: loss of Sti1 exacerbates Htt toxicity and hinders foci formation; elevation of Sti1 suppresses toxicity and organizes small Htt103Q foci into larger perinuclear assemblies containing thioflavin-T-positive amyloid-like material. High-copy suppressor screen in yeast, fluorescence microscopy, thioflavin-T staining, toxicity assays Molecular biology of the cell Medium 24109600
2014 Sti1/Hop is a dynamic elongated protein with a flexible N-terminal module and rigid C-terminal module; without Hsp90, Sti1 is more compact and TPR2B is the high-affinity Hsp70-binding site; in the presence of Hsp90, Hsp70 shifts its preference away from TPR2B; the linker connecting the two modules is crucial for Hsp70 interaction and client activation in vivo. Single-molecule fluorescence (FRET), NMR, truncation mutants, in vivo client activation assays, fluorescence cross-correlation spectroscopy Nature communications High 25851214
2014 Cytoplasmic STI1 directly interacts with the small GTPase Rnd1; this interaction is specific for Rnd1 (not other Rnd family members); STI1 overexpression prevents Rnd1-plexin-A1-mediated cytoskeleton retraction in COS collapse assay and enhances neurite outgrowth in PC-12 cells. Co-immunoprecipitation, COS cell collapse assay, PC-12 neurite outgrowth assay, specificity tests with Rnd family members Experimental cell research Medium 24690281
2014 Yeast Sti1 is phosphorylated at inhibitory sites; human Hop is also subject to inhibitory phosphorylation; phospho-mimetic variants of Hop have reduced ability to activate clients in vivo, reduced affinity for Hsp70, and reduced interaction with Hsp90 (for human Hop), inducing structural rearrangements in the protein core. Phospho-mimetic mutagenesis, in vivo client activation assays, affinity binding assays, structural analysis EMBO reports Medium 25504578
2016 STIP1 co-immunoprecipitates with actin from HEK293T cells and directly interacts with actin in vitro via its C-terminal TPR2AB-DP2 domain; STIP1 can stimulate actin ATPase activity in vitro; STIP1 depletion leads to increased nuclear actin accumulation, F-actin disorganization, and altered cofilin/profilin levels. Co-immunoprecipitation from HEK293T cells, in vitro direct binding/ATPase assay, STIP1 knockdown with fluorescence imaging of actin structures, western blot for cofilin and profilin International journal of molecular sciences Medium 32365744
2016 STIP1 interacts with the Axin scaffold protein, enhances the Axin–DVL2 interaction, and thereby activates β-catenin/TCF (Wnt) signaling in hepatocellular carcinoma cells. Co-immunoprecipitation, STIP1 knockdown/overexpression with downstream Wnt reporter Gene Low 29596884
2016 STIP1 domains DP1, TPR1, and TPR2A all contribute to PrPC binding: DP1 binds the N-terminal region of PrP (residues 23–95), TPR1 and TPR2A bind the C-terminal region (residues 90–231); only TPR1 and TPR2A directly inhibit AβO binding to PrPC and AβO-induced neuronal cell death; the TPR2A–PrP interface is extensive and partially overlaps with the Hsp90-binding site, suggesting a PrP–STIP1–Hsp90 ternary complex. NMR chemical shift mapping, binding domain mapping with truncated STIP1 constructs, cell death assays, amyloid-beta oligomer competition binding assays The Biochemical journal Medium 27208175
2016 Deletion of STI1 in yeast causes alterations in mitochondrial morphology and lower steady-state levels of a subset of mitochondrial proteins; double deletion of STI1 with mitochondrial import factors MIM1 or TOM20 shows synthetic growth phenotype; recombinant cytosolic domains of Tom20 and Tom70 bind Sti1 in vitro, suggesting Sti1 plays a direct or indirect role in mitochondrial protein import. Site-directed photo-crosslinking in yeast, genetic epistasis (double deletion growth assays), in vitro binding assay with Tom receptor domains, mitochondrial morphology imaging The FEBS journal Medium 27412066
2017 Three S100A1 dimers associate with one STIP1 molecule in a calcium-dependent manner; each STIP1 TPR domain (TPR1, TPR2A, TPR2B) binds one S100A1 dimer with different affinities (TPR2B highest); S100A1 binds each TPR domain through a common interface (α-helices III and IV) accessible only after calcium-induced conformational change; TPR2B binding involves insertion of S100A1 into its hydrophobic cleft. Isothermal titration calorimetry (ITC), domain-specific binding assays with isolated TPR domains, calcium-dependence studies The Biochemical journal High 28408431
2018 Hop/STIP1 depletion or overexpression reduces emerin protein levels via proteasomal and lysosomal pathways; Hop and emerin co-immunoprecipitate in a complex that also contains Hsp70 but not Hsp90; TPR2AB domain of Hop is required for the Hop-emerin association; loss of Hop or emerin causes nuclear deformation and decreased nuclear size; nuclear defects from Hop loss are rescued by emerin overexpression. Co-immunoprecipitation, STIP1 depletion/overexpression, proteasome/lysosome inhibitor experiments, nuclear morphology imaging, rescue experiment Biochemical and biophysical research communications Medium 30449594
2020 Human cell lines and budding yeast with deletion of STIP1/STI1 display reduced proteasome activity due to inefficient capping of the 20S core particle with regulatory particles; unexpectedly, knockout cells are more proficient at preventing protein aggregation and promoting protein refolding, because a more efficient prokaryote-like Hsp70–Hsp90 binary complex (without Hop restraint) compensates; this was also demonstrated in vitro. Gene knockout in human cells and yeast, in vitro reconstitution of Hsp70–Hsp90 chaperone activity, proteasome activity assays, protein aggregation/refolding assays Nature communications High 33239621
2021 STI1 co-immunoprecipitates α-synuclein; NMR analyses show direct interaction of α-synuclein with the TPR2A domain (but not TPR1 or TPR2B) of STI1, involving the C-terminal domain of α-synuclein; the STI1 TPR2A domain facilitates S129 phosphorylation of α-synuclein by Polo-like kinase 3 in vitro; mice over-expressing STI1 and Hsp90β show elevated S129 α-synuclein phosphorylation and inclusion formation; reduced STI1 function decreases inclusion formation and phosphorylation while mitigating motor and cognitive deficits. Co-immunoprecipitation, NMR interaction mapping, in vitro phosphorylation assay with PLK3, mouse model with altered STI1 expression Acta neuropathologica High 36121476
2021 Hsp90 and its co-chaperone Sti1 modulate TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity; Sti1 specifically interacts with TDP-43 and strongly modulates TDP-43 toxicity in a dose-dependent manner in yeast and mammalian neuronal cells. Co-immunoprecipitation, TDP-43 aggregation assay, toxicity assays in yeast and mammalian neuronal cells, genetic manipulations of STI1/Hsp90 FASEB journal Medium 33908654
2021 STIP1 can be isolated in a complex with actin and Hsp90 from HEK293T cells; STIP1 directly interacts with actin via the C-terminal TPR2AB-DP2 domain in vitro; STIP1 can stimulate the in vitro ATPase activity of actin. Co-immunoprecipitation, in vitro direct binding assay, in vitro ATPase stimulation assay International journal of molecular sciences Medium 32365744
2022 JAK2 phosphorylates STIP1 at tyrosine residues Y134 and Y152, promoting STIP1 protein stability, inducing nuclear-cytoplasmic shuttling, and promoting STIP1 secretion into the extracellular space; JAK2-mediated STIP1 phosphorylation enhances cell viability and increases resistance to cisplatin-induced cell death; disrupting STIP1–JAK2 interaction decreases JAK2 protein levels. Site-directed mutagenesis of phosphorylation sites, cell-penetrating inhibitory peptides, immunoblotting for stability, nuclear-cytoplasmic fractionation, ELISA for secretion, cell viability assays International journal of molecular sciences Medium 35269562
2023 STIP1 binds to HSP40, HSP70, and HSP90 in rat H9c2 cardiomyocytes; overexpression of STIP1 promotes the transition of Cx43 from Cx43-HSP70 to Cx43-HSP90 complexes and inhibits Cx43 ubiquitination; knockdown of STIP1 has the opposite effect; HSP90 inhibition counteracts the inhibitory effect of STIP1 overexpression on Cx43 ubiquitination. Co-immunoprecipitation, STIP1 overexpression/knockdown, HSP90 inhibitor treatment, ubiquitination assays in H9c2 cardiomyocytes Cytotechnology Medium 37187948
2023 The lncRNA LINC01226 binds STIP1 protein, leads to disassembly of the STIP1–HSP90 complex, elevates HSP90–β-catenin interactions, stabilizes β-catenin protein, and activates Wnt/β-catenin signaling to promote gastric cancer progression. RNA-protein pulldown, co-immunoprecipitation, LINC01226 overexpression/knockdown with downstream β-catenin/TCF assays Cancer letters Low 37806517
2024 During proteostatic stress, Sti1 forms cytoplasmic inclusions in yeast and mammalian cells that overlap with misfolded proteins; deletion of STI1 causes accumulation of soluble misfolded ubiquitinated proteins and activates the heat shock response; Sti1 sequesters misfolded proteins during stress independently of its Hsp90 ATPase regulatory function. Fluorescence imaging of inclusions in yeast and mammalian cells, soluble/insoluble protein fractionation, ubiquitin accumulation assay, heat shock reporter assay, STI1 deletion The FEBS journal Medium 39739753
2025 The mitochondrial targeting signal (MTS) directly engages the co-chaperones of Hsc70 including Stip1/HOP via site-specific photo-crosslinking; STIP1/Hop and St13 facilitate chaperone retention on the mature domain of mitochondrial precursor proteins; during acute import stress, this Hsp90 co-chaperone interaction (requiring the MTS) buffers precursor degradation and maintains import competence. Site-specific photo-crosslinking in cells, biochemical reconstitution, import stress experiments bioRxiv (preprint)preprint Medium bio_10.1101_2025.01.18.633710
2025 STIP1/HOP directly interacts with α-synuclein via two binding motifs in the C-terminus of α-synuclein that dynamically compete for the TPR2A domain of STIP1; STIP1 binding attenuates α-synuclein fibril formation while promoting accumulation of high-molecular-weight amorphous and A11-positive oligomeric species that are more cytotoxic to neuronal cells. NMR interaction mapping, in vitro aggregation assays, A11 oligomer dot-blot, neuronal cell viability assays bioRxiv (preprint)preprint Medium bio_10.1101_2025.03.26.645247
2025 STIP1 interacts with adenosylhomocysteinase (AHCY/SAHH) and changes AHCY conformation; STIP1 facilitates AHCY binding to lactate dehydrogenase A (LDHA), stimulating glycolysis; AHCY then recruits PRMT3 to methylate LDHA at R106, inhibiting ubiquitination-mediated AHCY degradation; STIP1 knockout in mice inhibits 4NQO-induced esophageal tumorigenesis. Co-immunoprecipitation, conformational assay, in vivo mouse knockout, glycolysis assays, methylation assays Exploration (Beijing, China) Low 41163796

Source papers

Stage 0 corpus · 96 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1989 Isolation and characterization of STI1, a stress-inducible gene from Saccharomyces cerevisiae. Molecular and cellular biology 214 2674681
1997 In vivo analysis of the Hsp90 cochaperone Sti1 (p60). Molecular and cellular biology 193 8972212
2012 The architecture of functional modules in the Hsp90 co-chaperone Sti1/Hop. The EMBO journal 184 22227520
2003 Sti1 is a non-competitive inhibitor of the Hsp90 ATPase. Binding prevents the N-terminal dimerization reaction during the atpase cycle. The Journal of biological chemistry 156 12525481
2010 The Hop/Sti1-Hsp90 chaperone complex facilitates the maturation and transport of a PAMP receptor in rice innate immunity. Cell host & microbe 143 20227662
1992 Molecular cloning and expression of a transformation-sensitive human protein containing the TPR motif and sharing identity to the stress-inducible yeast protein STI1. The Journal of biological chemistry 130 1569099
2020 The Hsp70-Hsp90 co-chaperone Hop/Stip1 shifts the proteostatic balance from folding towards degradation. Nature communications 104 33239621
2005 Independent regulation of Hsp70 and Hsp90 chaperones by Hsp70/Hsp90-organizing protein Sti1 (Hop1). The Journal of biological chemistry 89 16100115
2012 Dynamics of the regulation of Hsp90 by the co-chaperone Sti1. The EMBO journal 84 22354036
2000 A Stat3-interacting protein (StIP1) regulates cytokine signal transduction. Proceedings of the National Academy of Sciences of the United States of America 84 10954736
2009 The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. The Journal of allergy and clinical immunology 80 19254810
1998 CNS1 encodes an essential p60/Sti1 homolog in Saccharomyces cerevisiae that suppresses cyclophilin 40 mutations and interacts with Hsp90. Molecular and cellular biology 78 9819421
2007 STI1 promotes glioma proliferation through MAPK and PI3K pathways. Glia 75 17886292
2015 Hsp90 regulates the dynamics of its cochaperone Sti1 and the transfer of Hsp70 between modules. Nature communications 70 25851214
2007 Definition of the minimal fragments of Sti1 required for dimerization, interaction with Hsp70 and Hsp90 and in vivo functions. The Biochemical journal 67 17300223
2004 Sti1 and Cdc37 can stabilize Hsp90 in chaperone complexes with a protein kinase. Molecular biology of the cell 67 14742721
2006 Nucleotide-dependent interaction of Saccharomyces cerevisiae Hsp90 with the cochaperone proteins Sti1, Cpr6, and Sba1. Molecular and cellular biology 66 17101799
2010 Sti1 regulation of Hsp70 and Hsp90 is critical for curing of Saccharomyces cerevisiae [PSI+] prions by Hsp104. Molecular and cellular biology 62 20479121
2016 The cytosolic cochaperone Sti1 is relevant for mitochondrial biogenesis and morphology. The FEBS journal 56 27412066
2013 The Hsp70/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins. Molecular biology of the cell 51 24109600
2005 PrP cooperates with STI1 to regulate SOD activity in PrP-deficient neuronal cell line. Biochemical and biophysical research communications 49 15670743
2021 The Hsp70-Hsp90 go-between Hop/Stip1/Sti1 is a proteostatic switch and may be a drug target in cancer and neurodegeneration. Cellular and molecular life sciences : CMLS 48 34677645
2012 The Hsp90-Sti1 interaction is critical for Leishmania donovani proliferation in both life cycle stages. Cellular microbiology 48 23107115
2005 Effect of mutation of the tetratricopeptide repeat and asparatate-proline 2 domains of Sti1 on Hsp90 signaling and interaction in Saccharomyces cerevisiae. Genetics 45 16219779
2009 C. elegans STI-1, the homolog of Sti1/Hop, is involved in aging and stress response. Journal of molecular biology 43 19467242
2014 Hop/Sti1 phosphorylation inhibits its co-chaperone function. EMBO reports 33 25504578
2021 Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 33908654
2002 The Hsp90 co-chaperones Cdc37 and Sti1 interact physically and genetically. Biological chemistry 31 12437126
2017 Autocrine STIP1 signaling promotes tumor growth and is associated with disease outcome in hepatocellular carcinoma. Biochemical and biophysical research communications 29 28887036
2017 Autocrine and paracrine STIP1 signaling promote osteolytic bone metastasis in renal cell carcinoma. Oncotarget 26 28199984
2022 Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo. Acta neuropathologica 25 36121476
2015 Hyperactivity and attention deficits in mice with decreased levels of stress-inducible phosphoprotein 1 (STIP1). Disease models & mechanisms 25 26398952
2021 The STI1-domain is a flexible alpha-helical fold with a hydrophobic groove. Protein science : a publication of the Protein Society 24 33620121
2021 STIP1 knockdown suppresses colorectal cancer cell proliferation, migration and invasion by inhibiting STAT3 pathway. Chemico-biological interactions 23 33766539
2020 STIP1 down-regulation inhibits glycolysis by suppressing PKM2 and LDHA and inactivating the Wnt/β-catenin pathway in cervical carcinoma cells. Life sciences 23 32777299
2018 STIP1 is over-expressed in hepatocellular carcinoma and promotes the growth and migration of cancer cells. Gene 23 29596884
2023 LINC01226 promotes gastric cancer progression through enhancing cytoplasm-to-nucleus translocation of STIP1 and stabilizing β-catenin protein. Cancer letters 20 37806517
2021 Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia. Journal of neurology 20 33417001
2019 STIP1 Regulates Proliferation and Migration of Lung Adenocarcinoma Through JAK2/STAT3 Signaling Pathway. Cancer management and research 20 31819639
2016 The Hsp90 Co-chaperones Sti1, Aha1, and P23 Regulate Adaptive Responses to Antifungal Azoles. Frontiers in microbiology 20 27761133
2014 Polyglutamine-rich suppressors of huntingtin toxicity act upstream of Hsp70 and Sti1 in spatial quality control of amyloid-like proteins. PloS one 20 24828240
2017 Hop/Sti1 - A Two-Faced Cochaperone Involved in Pattern Recognition Receptor Maturation and Viral Infection. Frontiers in plant science 19 29075278
2016 Domains of STIP1 responsible for regulating PrPC-dependent amyloid-β oligomer toxicity. The Biochemical journal 19 27208175
2009 Reciprocal remodeling upon binding of the prion protein to its signaling partner hop/STI1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 19703931
2020 Knockdown of STIP1 inhibits the invasion of CD133‑positive cancer stem‑like cells of the osteosarcoma MG63 cell line via the PI3K/Akt and ERK1/2 pathways. International journal of molecular medicine 17 33125116
2019 Modulation of hippocampal neuronal resilience during aging by the Hsp70/Hsp90 co-chaperone STI1. Journal of neurochemistry 17 31562773
2014 STI1 antagonizes cytoskeleton collapse mediated by small GTPase Rnd1 and regulates neurite growth. Experimental cell research 17 24690281
2020 STIP1/HOP Regulates the Actin Cytoskeleton through Interactions with Actin and Changes in Actin-Binding Proteins Cofilin and Profilin. International journal of molecular sciences 16 32365744
2006 Expression of stress inducible protein 1 (Stip1) in the mouse testis. Molecular reproduction and development 16 16894550
2020 Serum STIP1, a Novel Indicator for Microvascular Invasion, Predicts Outcomes and Treatment Response in Hepatocellular Carcinoma. Frontiers in oncology 15 32426271
2017 Serum Autoantibodies against STIP1 as a Potential Biomarker in the Diagnosis of Esophageal Squamous Cell Carcinoma. Disease markers 15 28852266
2013 Expression and clinical significance of STIP1 in papillary thyroid carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 15 24163084
2007 Hop/STI1 modulates retinal proliferation and cell death independent of PrPC. Biochemical and biophysical research communications 15 17651690
2020 GOLPH3 Promotes Cancer Growth by Interacting With STIP1 and Regulating Telomerase Activity in Pancreatic Ductal Adenocarcinoma. Frontiers in oncology 13 33134174
2019 STIP1 Tissue Expression Is Associated with Survival in Chemotherapy-Treated Bladder Cancer Patients. Pathology oncology research : POR 13 31250373
2019 Down-regulation of STIP1 regulate apoptosis and invasion of glioma cells via TRAP1/AKT signaling pathway. Cancer genetics 12 31447061
2022 Comparative proteomics identify HSP90A, STIP1 and TAGLN-2 in serum extracellular vesicles as potential circulating biomarkers for human adenomyosis. Experimental and therapeutic medicine 11 35495589
2020 Cephalic Neuronal Vesicle Formation is Developmentally Dependent and Modified by Methylmercury and sti-1 in Caenorhabditis elegans. Neurochemical research 11 33037975
2022 Parkinson's Disease-Specific Autoantibodies against the Neuroprotective Co-Chaperone STIP1. Cells 10 35626686
2021 Proteomic Analysis Reveals That Metformin Suppresses PSMD2, STIP1, and CAP1 for Preventing Gastric Cancer AGS Cell Proliferation and Migration. ACS omega 10 34124444
2022 JAK2-Mediated Phosphorylation of Stress-Induced Phosphoprotein-1 (STIP1) in Human Cells. International journal of molecular sciences 9 35269562
2019 GLCCI1 and STIP1 variants are associated with asthma susceptibility and inhaled corticosteroid response in a Tunisian population. The Journal of asthma : official journal of the Association for the Care of Asthma 9 31516081
2018 Hop/STIP1 depletion alters nuclear structure via depletion of nuclear structural protein emerin. Biochemical and biophysical research communications 9 30449594
2017 Molecular basis for the interaction between stress-inducible phosphoprotein 1 (STIP1) and S100A1. The Biochemical journal 9 28408431
2017 Involvement of STI1 protein in the differentiation process of Trypanosoma cruzi. Parasitology international 9 29081390
2016 Low sequence identity but high structural and functional conservation: The case of Hsp70/Hsp90 organizing protein (Hop/Sti1) of Leishmania braziliensis. Archives of biochemistry and biophysics 9 27103305
2020 Effects of STIP1 and GLCCI1 polymorphisms on the risk of childhood asthma and inhaled corticosteroid response in Chinese asthmatic children. BMC pulmonary medicine 7 33208131
2016 Stress-Inducible Protein 1 (STI1): Extracellular Vesicle Analysis and Quantification. Methods in molecular biology (Clifton, N.J.) 7 27665558
2024 Stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) sequesters misfolded proteins during stress. The FEBS journal 6 39739753
2023 Molecular chaperones HSP40, HSP70, STIP1, and HSP90 are involved in stabilization of Cx43. Cytotechnology 6 37187948
2014 Systematic study of stress-inducible protein 1 (Stip1) in male reproductive system and its expression during stress response. Gene 6 25311551
2018 Loss of STI1-mediated neuronal survival and differentiation in disease-associated mutations of prion protein. Journal of neurochemistry 5 29337365
2011 Co-variation of STI1 and WDR36/UTP21 alters cell proliferation in a glaucoma model. Molecular vision 5 21850170
2024 Hsp70-Hsp90 organising protein (HOP/STIP1) is required for KSHV lytic replication. The Journal of general virology 4 39607759
2022 The Modulatory Role of sti-1 in Methylmercury-Induced Toxicity in Caenorhabditis elegans. Neurotoxicity research 4 35471723
2015 Identification of novel putative-binding proteins for cellular prion protein and a specific interaction with the STIP1 homology and U-Box-containing protein 1. Prion 4 26237451
2012 ¹H, ¹⁵N and ¹³C backbone resonance assignments of the TPR1 and TPR2A domains of mouse STI1. Biomolecular NMR assignments 4 23070844
2006 Novel interaction between HMGA1a and StIP1 in murine terminally differentiated retina. Molecular and cellular neurosciences 4 16870469
2025 STI1 domain dynamically engages transient helices in disordered regions to drive self-association and phase separation of yeast ubiquilin Dsk2. bioRxiv : the preprint server for biology 3 40161686
2025 STIP1 drives Metabolic Reprogramming in Esophageal Squamous Cell Carcinoma via AHCY-LDHA Axis. Exploration (Beijing, China) 3 41163796
2024 GOLPH3-STIP1 Complex Activates STAT3 Through Exosome Secretion to Induce Colon Cancer Metastasis. Biotechnology journal 3 39711092
2021 Intracellular targeting of STIP1 inhibits human cancer cell line growth. Translational cancer research 3 35116457
2019 Expression pattern of heat shock protein 90AB (HSP90AB) and stress-inducible protein 1 (Stip1) during spermatogenesis of mudskipper Boleophthalmus pectinirostris. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 3 30735774
2026 STI1 domain engages transient helices to mediate Dsk2 phase separation and proteasome condensation. The EMBO journal 2 41673446
2025 New insights into Sti1/Hop's cochaperone function highlight the complexity of proteostatic regulation. The FEBS journal 2 40259657
2024 Staphylococcus aureus infection initiates hypoxia-mediated STIP1 homology and U-box containing protein 1 upregulation to trigger osteomyelitis. Toxicon : official journal of the International Society on Toxinology 2 39059559
2017 New insight on the S100A1-STIP1 complex highlights the important relationship between allostery and entropy in protein function. The Biochemical journal 2 28819010
2025 Roles of Sti1, a homolog to mammalian Hop, in conidiation, environmental adaptation, and virulence of Beauveria bassiana. Fungal biology 1 40707123
2024 Polymorphism in Genes Encoding Adaptor Proteins ST13 and STIP1 and the Risk of Ischemic Stroke: a Pilot Study. Bulletin of experimental biology and medicine 1 38492099
2026 The protein co-chaperone STI-1 impacts motor function in C. elegans upon developmental methylmercury exposure. Neurotoxicology 0 41905501
2026 STI1 domains coordinate partitioning of UBQLN2 into stress-induced condensates. bioRxiv : the preprint server for biology 0 41959388
2026 Sti1 participates in the dynamics of protein aggregation triggered by glucose signaling in Saccharomyces cerevisiae. Acta biochimica et biophysica Sinica 0 42178287
2025 Doublecortin-like kinase 1, regulated by STIP1 homology and U-box containing protein 1 or Sp1 transcription factor, affects the malignant behaviors and drug sensitivity in adriamycin-resistant breast cancer cells. Naunyn-Schmiedeberg's archives of pharmacology 0 40257489
2025 Stress-inducible phosphoprotein 1 (STIP1) is a critical stemness regulator in mouse embryonic stem cells and early mammalian development. Communications biology 0 40883424
1997 [The isolation of the surface antigen from vegetative cells of Bacillus anthracis STI-1 and study of its protective properties]. Zhurnal mikrobiologii, epidemiologii i immunobiologii 0 9221667
1995 [The isolation and purification of the protective antigen and the edema factor from the culture filtrate of Bacillus anthracis STI-1]. Meditsinskaia parazitologiia i parazitarnye bolezni 0 8587516

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