Affinage

CACYBP

Calcyclin-binding protein · UniProt Q9HB71

Length
228 aa
Mass
26.2 kDa
Annotated
2026-06-09
72 papers in source corpus 35 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CacyBP/SIP (CACYBP) is a multidomain, Ca2+-responsive scaffold whose subcellular distribution and partner repertoire determine which of several regulatory programs it executes — protein degradation, MAP kinase dephosphorylation, cytoskeletal organization, chaperoning, and autophagy (PMID:12042313, PMID:29099417). Through its C-terminal region it binds multiple S100 proteins (S100A1, S100A6, S100A12, S100B, S100P) in a Ca2+-dependent manner (PMID:12042313), and S100A6 binding controls Ca2+-induced nuclear translocation that switches its activity (PMID:29534068). As a component of a Siah-1/Skp1-containing ubiquitin ligase complex, CacyBP/SIP drives proteasomal degradation of β-catenin and of p27Kip1, with the Skp1-binding domain required for nuclear p27Kip1 turnover and antiproliferative output (PMID:12042313, PMID:16340196, PMID:17400182, PMID:22295074, PMID:35184390, PMID:28196083, PMID:29024247); it likewise channels other substrates including mutant p53 (via Mdm2), OTUD5, and the MyD88 stability decision toward distinct cancer phenotypes (PMID:32880469, PMID:38558058, PMID:37968706). Independently, CacyBP/SIP is an intrinsic PP2A-like phosphatase that binds and dephosphorylates ERK1/2 (C-terminal region; E217K abolishes binding and activity) and p38 (via its CS domain), an activity negatively regulated by CK II phosphorylation at T184 and competitively antagonized by S100A6 (PMID:19166809, PMID:21110948, PMID:26085436, PMID:28283909). The protein also directly remodels the cytoskeleton: its N-terminal domain binds and polymerizes actin, it binds tropomyosin and modulates actin-activated myosin S1 ATPase, and it can bridge actin and tubulin networks (PMID:20637809, PMID:23266554). CacyBP/SIP further acts as an HSP90 co-chaperone and protects α-synuclein from aggregation through its N-terminal/CS region, and promotes autophagy by stabilizing BRUCE/Apollon and facilitating autophagic flux (PMID:29660399, PMID:33049998, PMID:31213539). A nuclear role encompasses NPM1 binding/phosphorylation and nucleolar maintenance under stress, plus RPL6 interaction that supports translation efficiency (PMID:29806702, PMID:40691326). A heterozygous CACYBP p.E177Q variant segregates with paucity of interlobular bile ducts in a dominant family, consistent with altered β-catenin degradation during bile duct maturation (PMID:35087201).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Established CacyBP/SIP's first defined molecular function — that it is not merely an S100-binding protein but a structural component of a ubiquitin ligase that targets β-catenin for degradation.

    Evidence Co-IP and ubiquitination assays placing SIP in a Siah-1/Skp1 complex, referenced and confirmed across multiple cancer models

    PMID:12042313 PMID:16340196 PMID:17400182 PMID:22295074 PMID:35184390

    Open questions at the time
    • Stoichiometry and assembly order of the Siah-1/Skp1/CacyBP complex not resolved
    • Does not address how Ca2+/S100 status gates ligase assembly
  2. 2002 High

    Defined the calcium-sensing input by mapping Ca2+-dependent S100 binding to a discrete C-terminal segment, establishing CacyBP/SIP as a Ca2+/S100-regulated effector.

    Evidence Affinity chromatography, overlay assays, and Co-IP from brain/tumor extracts with domain mapping (residues 155–229)

    PMID:12042313

    Open questions at the time
    • Functional consequence of each S100 partner not individually dissected
    • S100A6 selectivity over other S100s mechanistically unexplained
  3. 2010 High

    Revealed that CacyBP/SIP carries an intrinsic enzymatic activity — a PP2A-like phosphatase acting on ERK1/2 — defining a degradation-independent signaling function.

    Evidence In vitro phosphatase kinetics (p-NPP), okadaic acid inhibition, E217K mutagenesis, plus prior ERK1/2 direct-binding mapping

    PMID:19166809 PMID:21110948

    Open questions at the time
    • Catalytic mechanism and active-site residues not structurally defined
    • Physiological substrate range beyond ERK1/2 not established
  4. 2010 High

    Showed CacyBP/SIP directly organizes the cytoskeleton, polymerizing actin via its N-terminus and potentially linking actin and tubulin networks.

    Evidence Zero-length cross-linking, co-sedimentation, immunofluorescence co-localization, and domain fragment analysis in NB2a cells

    PMID:20637809

    Open questions at the time
    • In vivo relevance of actin/tubulin bridging not demonstrated
    • Regulation of cytoskeletal binding by Ca2+/S100 untested
  5. 2012 High

    Extended cytoskeletal function to thin-filament regulation, showing tropomyosin binding and modulation of actin-activated myosin ATPase.

    Evidence Fluorescence binding, electron microscopy, and myosin S1 ATPase assays with reconstituted actin/tropomyosin

    PMID:23266554

    Open questions at the time
    • Physiological context (muscle vs non-muscle) of thin-filament regulation unclear
    • Connection to motility phenotypes not directly tested
  6. 2016 High

    Identified the regulatory switch governing phosphatase activity — CK II phosphorylation at T184 suppresses it, and S100A6 blocks that phosphorylation, integrating kinase and Ca2+ inputs.

    Evidence In vitro CKII kinase assay, T184E/T184A phosphomimetic mutagenesis, and phosphatase readout in NB2a cells

    PMID:26085436

    Open questions at the time
    • Whether other phosphosites tune activity not addressed
    • In vivo CKII regulation in non-neuronal cells untested
  7. 2017 Medium

    Broadened phosphatase specificity to p38 and tied it to oxidative-stress responses, with the CS domain as the catalytic module.

    Evidence Reciprocal Co-IP, domain-mapped in vitro phosphatase assay, and phospho-p38 Westerns under H2O2 in NB2a cells

    PMID:28283909

    Open questions at the time
    • Reconciliation of CS-domain p38 dephosphorylation with C-terminal ERK1/2 activity not made
    • Stress-dependent activation mechanism unresolved
  8. 2014 Medium

    Connected localization to function — gastrin-triggered nuclear translocation drives cell-cycle progression and proliferation, establishing localization as the key functional determinant.

    Evidence Fractionation, immunofluorescence, siRNA blockade of translocation, and proliferation/cell-cycle assays in gastric cancer cells

    PMID:25110433

    Open questions at the time
    • Nuclear import machinery for CacyBP/SIP not identified
    • Direct nuclear targets after translocation only partly defined
  9. 2018 Medium

    Established the Ca2+/S100A6/cell-cycle logic of translocation — S100A6 binding is required for Ca2+-induced nuclear entry, and translocation in G2 increases Siah-1/Skp1 binding while lowering β-catenin and p-ERK1/2.

    Evidence Cell-cycle synchronization, Co-IP under varying Ca2+, S100A6 knockdown, and ΔS100 domain mutants with LiCl rescue across colon and gastric cancer cells

    PMID:27099442 PMID:28196083 PMID:29099417 PMID:29534068

    Open questions at the time
    • Direct evidence linking phosphorylation state to nuclear retention incomplete
    • Mostly single-lab cancer-cell systems
  10. 2019 High

    Defined a proteostasis role in autophagy — CacyBP/SIP stabilizes BRUCE/Apollon and, with Rab8, redirects it for autophagic destruction to promote clearance of damaged mitochondria and aggregates.

    Evidence Co-IP, ubiquitination assays, KO cells, autophagy/mitophagy flux assays, and live-cell BRUCE trafficking

    PMID:31213539

    Open questions at the time
    • How starvation switches CacyBP/SIP from protective to pro-degradative not fully resolved
    • Selectivity of cargo clearance untested
  11. 2020 High

    Defined CacyBP/SIP as an HSP90 co-chaperone and direct anti-aggregation factor for α-synuclein, expanding it from a degradation adaptor to a folding guardian.

    Evidence Hsp90 Co-IP, Hsf1 ChIP on the CACYBP promoter, ThT/EM/ultracentrifugation aggregation assays with purified proteins, PLA, and viability assays

    PMID:29660399 PMID:33049998

    Open questions at the time
    • Client range of the Hsp90 co-chaperone activity not catalogued
    • Relationship between chaperone and phosphatase domains unclear
  12. 2018 Medium

    Uncovered nuclear/nucleolar functions through NPM1 binding, S125 phosphorylation, rRNA association, and maintenance of nucleolar integrity under stress.

    Evidence Mass spectrometry, Co-IP, RIP, and fibrillarin immunofluorescence under oxidative stress

    PMID:29806702

    Open questions at the time
    • Kinase responsible for NPM1 S125 phosphorylation downstream of CacyBP/SIP not identified
    • Direct vs indirect role in rRNA binding unresolved
  13. 2022 Medium

    Expanded the substrate/partner network across cancers — mutant p53 (via Mdm2), OTUD5, MyD88 stabilization, and CACYBP isoform switching all feed proliferation, immune microenvironment, and β-catenin signaling.

    Evidence Co-IP, ubiquitination assays, ChIP for histone marks, RIP-seq, and xenograft/PDX models across glioma, LUAD, HCC, and myeloma

    PMID:29024247 PMID:32880469 PMID:35184390 PMID:37968706 PMID:38558058

    Open questions at the time
    • Many partners shown in single cancer-type studies without cross-validation
    • Whether these reflect the same ligase complex or distinct activities unclear
  14. 2022 Low

    Provided the first human disease link, associating a heterozygous CACYBP p.E177Q variant with paucity of interlobular bile ducts through altered β-catenin degradation.

    Evidence Family next-generation sequencing and IHC for CACYBP and β-catenin in patient liver

    PMID:35087201

    Open questions at the time
    • No in vitro reconstitution confirming enhanced ligase activity of the variant
    • Single family; causality not functionally proven
  15. 2025 Medium

    Connected CacyBP/SIP to translation and neurodevelopment — RPL6 binding supports protein-synthesis efficiency, and loss restrains neurite branching during cortical development.

    Evidence Mass spectrometry/Co-IP with OPP nascent-peptide labeling and Hsp70 induction; lentiviral shRNA knockdown with morphometry in opossum cortical neurons

    PMID:40476326 PMID:40691326

    Open questions at the time
    • Mechanism by which RPL6 binding alters translation undefined
    • Neurodevelopmental phenotype shown only in marsupial model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single protein arbitrates among ligase, phosphatase, cytoskeletal, chaperone, autophagy, and translational activities — and what structural/post-translational state selects each — remains unresolved.
  • No integrated structural model linking domain organization to the competing activities
  • No unified accounting of how Ca2+/S100A6, CKII phosphorylation, SUMOylation, and cell-cycle stage jointly set output
  • Many cancer-specific partnerships lack independent replication

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0016787 hydrolase activity 2 GO:0044183 protein folding chaperone 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005856 cytoskeleton 3 GO:0005730 nucleolus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9612973 Autophagy 2
Partners
ERK1/2HSP90MDM2NPM1RPL6S100A6SIAH1SKP1
Complex memberships
Siah-1/Skp1 ubiquitin ligase complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 CacyBP/SIP binds multiple S100 family proteins (S100A1, S100A6, S100A12, S100B, S100P but not S100A4, calbindin D9k, parvalbumin, or calmodulin) in a Ca2+-dependent manner, and this interaction occurs via the C-terminal fragment of CacyBP/SIP (residues 155–229). Co-immunoprecipitation from brain and tumor cell extracts confirmed physiological relevance. CacyBP/SIP affinity chromatography, nitrocellulose overlay assay with 125I-CacyBP/SIP, Co-immunoprecipitation from tissue/cell extracts The Journal of biological chemistry High 12042313
2001 CacyBP/SIP (identified as SIP) interacts with Siah-1 and Skp1 and functions as a component of a ubiquitin ligase complex that promotes proteasomal degradation of β-catenin. Referenced in multiple corpus abstracts as the foundational finding (Matsuzawa and Reed, Mol Cell 2001); confirmed in downstream studies by Co-immunoprecipitation and ubiquitination assays Molecular Cell (referenced; confirmed by multiple subsequent papers in corpus) High 12042313 16340196 17400182 22295074 35184390
2009 CacyBP/SIP directly binds ERK1/2 kinases; S100A6 competes for this interaction. A point mutant E217K of CacyBP/SIP does not bind ERK1/2 but retains S100A6 binding, implicating the C-terminal region (residues 189–219) in ERK1/2 binding. CacyBP/SIP–ERK1/2 interaction inhibits phosphorylation of the Elk-1 transcription factor in vitro and in the nuclear fraction of NB2a cells. Co-immunoprecipitation, site-directed mutagenesis (E217K), molecular modeling, in vitro kinase/phosphorylation assay, nuclear fractionation Biochemical and biophysical research communications High 19166809
2010 CacyBP/SIP exhibits intrinsic phosphatase activity toward ERK1/2; the E217K mutant lacks this activity. Km and Vmax for p-NPP substrate and inhibition by okadaic acid (IC50 ~45 nM) are consistent with a PP2A-like phosphatase. Sequence analysis reveals similarity to phosphatase-like proteins and MAP kinase phosphatases. In vitro phosphatase activity assay (p-NPP substrate), okadaic acid inhibition, E217K mutagenesis, sequence analysis Biochemical and biophysical research communications High 21110948
2010 CacyBP/SIP directly binds actin, co-localizes with actin in NB2a cells, induces G-actin polymerization and formation of circular actin filament bundles. The N-terminal fragment (residues 1–179) is sufficient for this activity; the C-terminal fragment (residues 178–229) is not. CacyBP/SIP can simultaneously interact with both tubulin and actin, suggesting it may link the two cytoskeletal networks. Zero-length cross-linking, co-sedimentation assay, immunofluorescence co-localization, proximity ligation assay, stable cell line overexpression with adhesion/migration readout, N- and C-terminal fragment analysis Biochimica et biophysica acta High 20637809
2012 CacyBP/SIP binds directly to tropomyosin, and binding to the actin–tropomyosin complex causes conformational changes in tropomyosin (increased fluorescence). CacyBP/SIP destabilizes actin filaments in the absence of tropomyosin, but tropomyosin reverses this effect. CacyBP/SIP reduces actin-activated myosin S1 ATPase activity, and tropomyosin enhances this inhibitory effect. Fluorescence assay with AEDANS-labeled tropomyosin, direct binding assay, electron microscopy, actin-activated myosin S1 ATPase colorimetric assay Biochimica et biophysica acta High 23266554
2007 CacyBP/SIP binds tubulin (established prior work cited by corpus), and in neurons its co-localization with tubulin and tau changes with age: in young rats CacyBP/SIP is present in cytoplasm and neuronal processes together with tubulin/tau; in aged rats it shifts to cytoplasm of neuronal somata, suggesting involvement in cytoskeletal physiology. Immunohistochemistry, immunofluorescence in cultured neurons and rat brain sections at multiple ages Journal of neural transmission Medium 18506390
2016 Casein kinase II (CKII) phosphorylates CacyBP/SIP at threonine 184 in vitro; S100A6 inhibits this phosphorylation in a Ca2+-dependent manner. The phosphomimetic T184E mutant has lower phosphatase activity toward p-ERK1/2 compared to T184A or wild-type, indicating that CKII-mediated phosphorylation at T184 negatively regulates CacyBP/SIP's phosphatase activity. In vitro phosphorylation assay (CKII), site-directed mutagenesis (T184E, T184A), Western blot in NB2a cells, phosphatase activity assay toward p-ERK1/2 Journal of cellular biochemistry High 26085436
2017 CacyBP/SIP binds and dephosphorylates p38 MAP kinase; the middle CS domain is responsible for p38 dephosphorylation. In NB2a cells treated with hydrogen peroxide, CacyBP/SIP-mediated dephosphorylation of phospho-p38 is more effective than in untreated cells, implicating CacyBP/SIP in oxidative stress responses. Co-immunoprecipitation from NB2a cell lysate and with recombinant proteins, in vitro phosphatase assay using domain fragments, Western blot for phospho-p38 under H2O2 stress Amino acids Medium 28283909
2013 CacyBP/SIP is sumoylated at lysine 16 in neuroblastoma NB2a cells; it binds the E2 SUMO ligase Ubc9 in cell extract. Uniquely, sumoylated CacyBP/SIP is found in the cytoplasmic rather than the nuclear fraction. Immunoprecipitation for SUMO-modified proteins, cell fractionation, site-directed identification of K16 as sumoylation site Neurochemical research Medium 24078263
2019 Under normal conditions, CacyBP/SIP (SIP) inhibits ubiquitination and proteasomal degradation of BRUCE/Apollon, likely by blocking Nrdp1 binding to BRUCE. Upon starvation, SIP together with Rab8 enhances translocation of BRUCE into the recycling endosome and promotes autophagic destruction of BRUCE by optineurin-mediated autophagy, thereby relieving BRUCE-mediated proteasomal degradation of LC3-I and stimulating autophagy. Deletion of SIP in cells reduces autophagic degradation of damaged mitochondria and cytosolic protein aggregates. Co-immunoprecipitation, ubiquitination assay, SIP knockout cell lines, autophagy flux assay (LC3-I/II), mitophagy assay, live-cell imaging of BRUCE trafficking with Rab8 Proceedings of the National Academy of Sciences of the United States of America High 31213539
2019 RNF41 binds CACYBP via its C-terminal substrate binding domain, ubiquitinates CACYBP, and promotes its degradation via both proteasome- and lysosome-dependent pathways. CACYBP overexpression stimulates Ser10, Thr157, and Thr198 phosphorylation of P27Kip1 and its cytoplasmic retention; RNF41 co-expression attenuates this. CACYBP depletion causes G1/S arrest and increased apoptosis in HCC cells. Co-immunoprecipitation (endogenous and exogenous), ubiquitination assay, Western blot for P27Kip1 phosphorylation, immunofluorescence for P27Kip1 localization, flow cytometry, xenograft model, P27Kip1-S10D/S10A reconstitution Theranostics High 31754404
2017 CacyBP/SIP nuclear translocation induced by gastrin promotes proteasome-dependent degradation of p27Kip1 in colon cancer cells. CacyBP/SIP binds Skp1 (shown by Co-IP); a CacyBP/SIP truncation mutant lacking the Skp1 binding site fails to promote p27Kip1 degradation even after nuclear translocation. Proteasome inhibitor MG132 prevents gastrin-induced p27Kip1 reduction. Co-immunoprecipitation, truncation mutagenesis, confocal immunofluorescence, Western blot, MG132 proteasome inhibitor, siRNA knockdown PloS one High 28196083
2016 CacyBP/SIP nuclear translocation in gastric cancer cells promotes proteasome-dependent p27Kip1 degradation; CacyBP/SIP binds Skp1 (Co-IP), and a Skp1-binding-deficient mutant of CacyBP/SIP fails to stimulate p27Kip1 degradation even when it translocates to the nucleus. G1-phase CacyBP/SIP is cytoplasmic; it translocates to nucleus at G2 where β-catenin and p-ERK1/2 are reduced. Co-immunoprecipitation, truncation mutagenesis, immunofluorescence, Western blot, MG132 proteasome inhibitor, cell cycle synchronization World journal of gastroenterology Medium 27099442
2018 Cell cycle-dependent nuclear translocation of CacyBP/SIP, Siah-1, and Skp1: these proteins are cytoplasmic in G1 and translocate to the nucleus in G2. In G2, CacyBP/SIP phosphorylation and binding capacity to Siah-1 and Skp1 increase, while β-catenin and p-ERK1/2 decrease. A CacyBP/SIP mutant lacking the S100-binding domain (CacyBP-ΔS100) shows increased nuclear translocation, further suppressing β-catenin and proliferation; this is reversed by β-catenin activator LiCl. Immunofluorescence after cell cycle synchronization, Co-immunoprecipitation, Western blot, phosphorylation assay, LiCl/XAV-939 pharmacological modulation Anti-cancer drugs Medium 29099417
2014 Gastrin stimulation triggers nuclear translocation of CacyBP/SIP in gastric cancer cells; CacyBP/SIP nuclear translocation promotes cell cycle progression from G1 phase and enhances proliferation. siRNA-mediated prevention of nuclear translocation abolishes these proliferative effects. Immunofluorescence, subcellular fractionation + Western blot, MTT assay, colony formation assay, flow cytometry cell cycle analysis, siRNA knockdown World journal of gastroenterology Medium 25110433
2018 Ca2+-dependent binding of S100A6 to CacyBP/SIP is required for Ca2+-induced nuclear translocation of CacyBP/SIP in colon cancer SW480 cells: ionomycin-elevated [Ca2+]i triggers translocation, and knockdown of S100A6 abolishes this effect. Immunofluorescence, Co-immunoprecipitation under varying [Ca2+], siRNA knockdown of S100A6 PloS one Medium 29534068
2017 CacyBP/SIP promotes Siah1-mediated ubiquitination and degradation of cytoplasmic p27Kip1, inhibiting glioma cell migration and invasion. Silencing CacyBP/SIP reduces the Siah1–p27 interaction and attenuates p27 ubiquitination; overexpression increases the Siah1–p27 interaction and p27 degradation. Siah1 knockdown blocks p27 degradation. Co-immunoprecipitation, ubiquitination assay, siRNA/overexpression of CacyBP/SIP and Siah1, migration/invasion assays (Transwell), Western blot Cell biology international Medium 29024247
2020 CacyBP/SIP interacts with Hsp90 and acts as a co-chaperone; overexpression of CacyBP/SIP in HEp-2 cells increases cellular resistance to stress-induced death. The Hsf1 transcription factor binds to the CacyBP/SIP gene promoter and up-regulates CacyBP/SIP expression under stress conditions (H2O2 and radicicol). Co-immunoprecipitation (CacyBP/SIP–Hsp90), ChIP assay (Hsf1 on CacyBP/SIP promoter), Western blot, cell viability assay, CacyBP/SIP overexpression The international journal of biochemistry & cell biology Medium 29660399
2020 CacyBP/SIP directly interacts with α-synuclein and protects it from aggregation at the initial phase of fibril formation. The fragment overlapping the N-terminal domain and CS domain of CacyBP/SIP is critical for this chaperone-like activity. In HEK293 cells overexpressing CacyBP/SIP, there are fewer α-synuclein inclusions and greater viability upon rotenone treatment. Thioflavin T fluorescence aggregation assay, high-speed ultracentrifugation + dot-blot, transmission electron microscopy, proximity ligation assay (PLA) in cells, in vitro assay with purified recombinant proteins, cell viability assay Cells High 33049998
2018 CacyBP/SIP interacts with NPM1 (nucleophosmin) directly; their complex is found in the cell nucleus. CacyBP/SIP overexpression favors phosphorylation of NPM1 on S125 and increases binding of 28S and 18S rRNA to NPM1. Under oxidative stress, CacyBP/SIP overexpression alters NPM1 nuclear distribution and maintains nucleolar structure (assessed by fibrillarin staining); CacyBP/SIP is required for preserving nucleolar integrity under stress. Mass spectrometry identification, Co-immunoprecipitation, direct binding assay, RNA immunoprecipitation (RIP), immunofluorescence (fibrillarin), Western blot Journal of cellular physiology Medium 29806702
2022 SFRS8 splicing factor mediates alternative splicing of CACYBP pre-mRNA, reducing isoform 1 (NM_014412.3) and increasing isoform 2 (NM_001007214.1). Isoform switching alters ubiquitination and degradation of β-catenin, promoting myeloma progression. Exosomal siRNA targeting CACYBP isoform 2 inhibits tumor growth in PDX models. RNA immunoprecipitation sequencing (RIP-seq), RIP-qPCR, Co-IP, xenograft models, PDX model, exosome-mediated siRNA delivery Clinical and translational medicine Medium 35184390
2023 CacyBP binds MyD88 via its Toll/IL-1 receptor (TIR) domain and protects MyD88 from Siah-1-mediated proteasomal degradation by competitive binding. CacyBP–MyD88 signaling promotes HDAC1-mediated H3K9ac and H3K27ac modifications on the CX3CL1 promoter, increasing CX3CL1 transcription and secretion in HCC cells, which enhances tumor-associated macrophage infiltration. CacyBP inhibition reduces immunosuppressive microenvironment and sensitizes tumors to anti-PD-1 therapy. Co-immunoprecipitation, immunofluorescence, Co-IP competition assay, in vitro and in vivo macrophage recruitment assays, chromatin immunoprecipitation (H3K9ac/H3K27ac on CX3CL1 promoter), xenograft models Journal of experimental & clinical cancer research Medium 37968706
2020 CacyBP/SIP promotes degradation of mutant p53 by enhancing Mdm2 E3 ubiquitin ligase activity in U251 glioma cells. CacyBP/SIP interacts with both p53 and Mdm2, increases p53 ubiquitination in a dose-dependent manner in the presence of Mdm2, and Mdm2 inhibition reverses this. In wild-type p53 U87 cells, CacyBP/SIP has no effect on proliferation or p53 levels. Co-immunoprecipitation (CacyBP/SIP with p53 and Mdm2), ubiquitination assay (dose–response), Mdm2 inhibitor treatment, Western blot, shRNA knockdown Neoplasma Medium 32880469
2016 CacyBP/SIP overexpression reduces p-ERK1/2 levels in undifferentiated NB2a cells, leading to decreased CREB phosphorylation and reduced BDNF mRNA; silencing has the opposite effect. In differentiated NB2a cells, CacyBP/SIP overexpression has a different effect on p-ERK1/2, which correlates with changes in CacyBP/SIP post-translational modifications and protein ligands. CacyBP/SIP overexpression and siRNA silencing, Western blot for p-ERK1/2, p-CREB, RT-qPCR for BDNF mRNA, 2D-PAGE analysis of CacyBP/SIP modification state Neurochemistry international Medium 27180052
2012 CacyBP/SIP exhibits phosphatase activity toward ERK1/2 in the nuclear fraction of undifferentiated NB2a cells but not in HCT116 colon cancer cells. The phosphorylation state of CacyBP/SIP differs between these cell lines (assessed by 2D-electrophoresis), and nuclear β-catenin levels are inversely correlated: low in NB2a (with CacyBP/SIP overexpression) and high in HCT116. CacyBP/SIP overexpression, nuclear fractionation, phosphatase activity assay, 2D-electrophoresis, Western blot Biochemistry and cell biology Medium 22480271
2012 S100A6 negatively regulates CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation. A CacyBP/SIP truncation mutant lacking the S100-binding domain (CacyBP/SIPΔS100) shows reduced S100A6 co-immunoprecipitation and further reduces proliferation and tumorigenesis compared to wild-type, demonstrating that S100A6 binding attenuates CacyBP/SIP's antiproliferative effect through modulation of β-catenin expression and Tcf/LEF transcriptional activity. Co-immunoprecipitation, truncation mutagenesis, MTT assay, FACS, clonogenic assay, tumor xenograft PloS one Medium 22295074
2017 NFAT1 transcription factor directly binds to the CacyBP/SIP gene promoter and up-regulates CacyBP/SIP expression; inhibition or stimulation of NFAT transcriptional activity correspondingly decreases or increases CacyBP/SIP levels. Western blot, RT-PCR, luciferase reporter assay, EMSA, chromatin immunoprecipitation (ChIP) Immunobiology Medium 28526484
2022 Heterozygous CACYBP/SIP p.E177Q variant is linked to paucity of interlobular bile ducts (PILBD) in a dominant family. CACYBP/SIP forms a ubiquitin ligase complex that degrades non-phosphorylated β-catenin; the variant may form a more active/stable complex, enhancing β-catenin degradation and delaying bile duct maturation. Next-generation sequencing (family), immunohistochemistry for CACYBP and β-catenin in patient liver Journal of human genetics Low 35087201
2024 CacyBP interacts directly with OTUD5 deubiquitinase, enhances ubiquitination and proteasomal degradation of OTUD5, and thereby promotes lung adenocarcinoma tumorigenesis. Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown functional assays (proliferation, migration, invasion), Western blot Carcinogenesis Medium 38558058
2025 CacyBP/SIP interacts directly with ribosomal protein RPL6; the interaction was confirmed by multiple biochemical methods and in silico domain mapping. Cells with stably silenced CacyBP/SIP show reduced perinuclear nascent polypeptide labeling (OPP staining) and lower Hsp70 induction after heat shock, suggesting CacyBP/SIP influences ribosome function and protein synthesis efficiency. Mass spectrometry, Co-immunoprecipitation, direct binding assay, in silico domain mapping, OPP (O-propargyl-puromycin) labeling of nascent polypeptides, Western blot for Hsp70 under heat shock in CacyBP/SIP-silenced vs. control cells Amino acids Medium 40691326
2025 CacyBP/SIP knockdown in cortical neurons of opossum (marsupial model) causes excessive branching and elongation of dendritic trees and axon arbors during upper cortical layer formation, without affecting proliferation or differentiation. This establishes a role for CacyBP/SIP in restraining neurite branching during cortical development. Lentiviral shRNA knockdown, primary cortical neuron cultures, morphometric analysis of dendritic and axonal arbors, cell proliferation and differentiation assays Journal of neurochemistry Medium 40476326
2025 CacyBP/SIP stabilization by Cordycepin (via inhibiting its ubiquitin-proteasome degradation) suppresses NLRP3 inflammasome activation and enhances autophagosome-lysosome fusion, leading to autophagic degradation of α-synuclein in rotenone-treated SH-SY5Y cells. Blockade of CacyBP/SIP abrogates these neuroprotective effects. CacyBP/SIP protein stability assay with proteasome inhibitors, NLRP3 inflammasome activation assay, autophagosome-lysosome fusion assay, α-synuclein aggregation assay, siRNA knockdown of CacyBP/SIP, in vivo rotenone mouse model Free radical biology & medicine Medium 40639630
2025 CacyBP interacts directly with CDK1 (co-immunoprecipitation); CDK1 overexpression rescues the inhibitory effects of CacyBP knockdown on LUAD cell growth. CacyBP promotes LUAD progression at least in part through CDK1-mediated activation of the PI3K/AKT pathway (PI3K inhibitor LY294002 blocks CDK1-mediated growth). Co-immunoprecipitation (CacyBP–CDK1), CDK1 overexpression rescue, LY294002 PI3K inhibition, proliferation/apoptosis/migration assays, xenograft model Biomolecules & biomedicine Medium 40167359

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 CacyBP/SIP, a calcyclin and Siah-1-interacting protein, binds EF-hand proteins of the S100 family. The Journal of biological chemistry 126 12042313
2013 iTRAQ based quantitative proteomics approach validated the role of calcyclin binding protein (CacyBP) in promoting colorectal cancer metastasis. Molecular & cellular proteomics : MCP 63 23543800
2015 CacyBP/SIP--Structure and variety of functions. Biochimica et biophysica acta 52 26493724
2019 SIP/CacyBP promotes autophagy by regulating levels of BRUCE/Apollon, which stimulates LC3-I degradation. Proceedings of the National Academy of Sciences of the United States of America 50 31213539
2000 Calcyclin (S100A6) binding protein (CacyBP) is highly expressed in brain neurons. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 50 10950876
2007 Overexpressed CacyBP/SIP leads to the suppression of growth in renal cell carcinoma. Biochemical and biophysical research communications 47 17400182
2023 By integrating single-cell RNA-seq and bulk RNA-seq in sphingolipid metabolism, CACYBP was identified as a potential therapeutic target in lung adenocarcinoma. Frontiers in immunology 44 36776843
2010 S100A6 binding protein and Siah-1 interacting protein (CacyBP/SIP): spotlight on properties and cellular function. Amino acids 43 20182755
2010 Tubulin binding protein, CacyBP/SIP, induces actin polymerization and may link actin and tubulin cytoskeletons. Biochimica et biophysica acta 40 20637809
2009 CacyBP/SIP binds ERK1/2 and affects transcriptional activity of Elk-1. Biochemical and biophysical research communications 39 19166809
2018 Newcastle Disease Virus V Protein Inhibits Cell Apoptosis and Promotes Viral Replication by Targeting CacyBP/SIP. Frontiers in cellular and infection microbiology 36 30234028
2019 CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics 35 31754404
2010 CacyBP/SIP expression is involved in the clinical progression of breast cancer. World journal of surgery 35 20585948
2004 Regulation of drug sensitivity of gastric cancer cells by human calcyclin-binding protein (CacyBP). Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 32 15449204
2014 CacyBP/SIP protein is important for the proliferation of human glioma cells. IUBMB life 30 24740456
2005 S100A6 and CacyBP/SIP - two proteins discovered in ehrlich ascites tumor cells that are potentially involved in the degradation of beta-catenin. Chemotherapy 28 16340196
2011 CacyBP/SIP protein promotes proliferation and G1/S transition of human pancreatic cancer cells. Molecular carcinogenesis 27 21268134
2012 S100A6 protein negatively regulates CacyBP/SIP-mediated inhibition of gastric cancer cell proliferation and tumorigenesis. PloS one 26 22295074
2010 ERK1/2 is dephosphorylated by a novel phosphatase--CacyBP/SIP. Biochemical and biophysical research communications 26 21110948
2008 Expression and clinical significance of CacyBP/SIP in pancreatic cancer. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 24 18765951
2022 Splicing factor arginine/serine-rich 8 promotes multiple myeloma malignancy and bone lesion through alternative splicing of CACYBP and exosome-based cellular communication. Clinical and translational medicine 23 35184390
2017 CacyBP/SIP promotes the proliferation of colon cancer cells. PloS one 23 28196083
2008 Age-dependent changes in neuronal distribution of CacyBP/SIP: comparison to tubulin and the tau protein. Journal of neural transmission (Vienna, Austria : 1996) 21 18506390
2020 Ageing-related changes in the levels of β-catenin, CacyBP/SIP, galectin-3 and immunoproteasome subunit LMP7 in the heart of men. PloS one 20 32119722
2012 CacyBP/SIP phosphatase activity in neuroblastoma NB2a and colon cancer HCT116 cells. Biochemistry and cell biology = Biochimie et biologie cellulaire 20 22480271
2005 Expression and hormonal regulation of calcyclin-binding protein (CacyBP) in the mouse uterus during early pregnancy. Life sciences 20 16289137
2017 CacyBP/SIP inhibits the migration and invasion behaviors of glioblastoma cells through activating Siah1 mediated ubiquitination and degradation of cytoplasmic p27. Cell biology international 19 29024247
2012 CacyBP/SIP as a novel modulator of the thin filament. Biochimica et biophysica acta 19 23266554
2017 Stress-Dependent Changes in the CacyBP/SIP Interacting Protein S100A6 in the Mouse Brain. PloS one 18 28068373
2020 Comparative Assessment of the WNT/β-Catenin Pathway, CacyBP/SIP, and the Immunoproteasome Subunit LMP7 in Various Histological Types of Renal Cell Carcinoma. Frontiers in oncology 16 33330038
2013 CacyBP/SIP enhances multidrug resistance of pancreatic cancer cells by regulation of P-gp and Bcl-2. Apoptosis : an international journal on programmed cell death 16 23463283
2023 Blockage of CacyBP inhibits macrophage recruitment and improves anti-PD-1 therapy in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 15 37968706
2018 Sex differences in distribution of cannabinoid receptors (CB1 and CB2), S100A6 and CacyBP/SIP in human ageing hearts. Biology of sex differences 15 30482253
2018 Current view on cellular function of S100A6 and its ligands, CacyBP/SIP and Sgt1. Postepy biochemii 15 30656909
2014 CacyBP/SIP nuclear translocation induced by gastrin promotes gastric cancer cell proliferation. World journal of gastroenterology 15 25110433
2017 MAP kinase p38 is a novel target of CacyBP/SIP phosphatase. Amino acids 14 28283909
2021 Downregulation of CacyBP by CRISPR/dCas9-KRAB Prevents Bladder Cancer Progression. Frontiers in molecular biosciences 13 34179100
2020 HSP90 Co-Chaperone, CacyBP/SIP, Protects α-Synuclein from Aggregation. Cells 13 33049998
2016 The potential role of CacyBP/SIP in tumorigenesis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 26873490
2016 Distinct effect of CacyBP/SIP on the ERK1/2-CREB-BDNF pathway in undifferentiated and differentiated neuroblastoma NB2a cells. Neurochemistry international 13 27180052
2012 Up-regulation of CacyBP/SIP during rat breast cancer development. Breast cancer (Tokyo, Japan) 12 22926504
2018 CacyBP/SIP, a Hsp90 binding chaperone, in cellular stress response. The international journal of biochemistry & cell biology 11 29660399
2016 Influence of S100A6 on CacyBP/SIP Phosphorylation and Elk-1 Transcriptional Activity in Neuroblastoma NB2a Cells. Journal of cellular biochemistry 11 26085436
2006 Establishment and characterization of calcyclin binding protein (CacyBP) monoclonal antibody. Hybridoma (2005) 11 16704310
2020 CacyBP/SIP promotes tumor progression by regulating apoptosis and arresting the cell cycle in osteosarcoma. Experimental and therapeutic medicine 10 32742374
2015 Expression and regulation of CacyBP/SIP in chronic lymphocytic leukemia cell balances of cell proliferation with apoptosis. Journal of cancer research and clinical oncology 10 26603518
2018 Comparative evaluation of CacyBP/SIP protein, β-catenin, and immunoproteasome subunit LMP7 in the heart of rats with hypertension of different etiology. Experimental biology and medicine (Maywood, N.J.) 9 30472885
2016 CacyBP/SIP inhibits Doxourbicin-induced apoptosis of glioma cells due to activation of ERK1/2. IUBMB life 9 26825673
2015 Role of the CacyBP/SIP protein in gastric cancer. Oncology letters 9 26137007
2016 CacyBP/SIP nuclear translocation regulates p27Kip1 stability in gastric cancer cells. World journal of gastroenterology 7 27099442
2013 The CacyBP/SIP protein is sumoylated in neuroblastoma NB2a cells. Neurochemical research 7 24078263
2023 The Effect of CacyBP/SIP on the Phosphorylation of ERK1/2 and p38 Kinases in Clear Cell Renal Cell Carcinoma. International journal of molecular sciences 6 37373509
2021 [CacyBP promotes the proliferation and invasion of non-small cell lung cancer]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 6 34530574
2020 CacyBP/SIP in the rat spinal cord in norm and after transection - Influence on the phosphorylation state of ERK1/2 and p38 kinases. Neurochemistry international 6 32544715
2018 The effect of S100A6 on nuclear translocation of CacyBP/SIP in colon cancer cells. PloS one 6 29534068
2017 Regulation of CacyBP/SIP expression by NFAT1 transcription factor. Immunobiology 6 28526484
2022 CACYBP knockdown inhibits progression of prostate cancer via p53. Journal of cancer research and clinical oncology 5 36576589
2018 Cell cycle-dependent translocation and regulatory mechanism of CacyBP/SIP in gastric cancer cells. Anti-cancer drugs 5 29099417
2012 Identification and characterization of a novel calcyclin binding protein (CacyBP) gene from Apis cerana cerana. Molecular biology reports 5 22539186
2025 Cordycepin promotes autophagic degradation of α-synuclein via CacyBP/SIP activation for ameliorating olfactory dysfunction against Parkinson's disease. Free radical biology & medicine 3 40639630
2020 CacyBP/SIP protein reduces p53 stability by enhancing Mdm2 activity in p53 mutant glioma cells. Neoplasma 3 32880469
2018 Interaction of CacyBP/SIP with NPM1 and its influence on NPM1 localization and function in oxidative stress. Journal of cellular physiology 3 29806702
2023 Involvement of CacyBP/SIP in differentiation and the immune response of HaCaT keratinocytes. Immunobiology 2 37156124
2025 CacyBP/SIP Protein Regulates the Length and Branching of Neuronal Processes During Cortical Development. Journal of neurochemistry 1 40476326
2024 CacyBP promotes the development of lung adenocarcinoma by regulating OTUD5. Carcinogenesis 1 38558058
2024 Comparative assessment of CacyBP/SIP, β-catenin and cannabinoid receptors in the adrenals of hypertensive rats. Journal of cellular and molecular medicine 1 38780511
2023 Evaluation of the Expression and Localization of the Multifunctional Protein CacyBP/SIP and Elements of the MAPK Signaling Pathway in the Adrenal Glands of Rats with Primary and Secondary Hypertension. International journal of molecular sciences 1 38203261
2026 Analysis of CacyBP/SIP, ERK1/2, and p38 Expression in Low- and High-Grade Papillary Urothelial Carcinoma. Cancer medicine 0 41692428
2025 Silencing CACYBP suppresses lung adenocarcinoma growth via CDK1 inhibition. Biomolecules & biomedicine 0 40167359
2025 CacyBP/SIP - RPL6 interaction: potential influence on ribosome function. Amino acids 0 40691326
2024 Evaluation of CacyBP/SIP expression and its relationship with ERK1/2 and p38 kinase in testicular seminoma. Pathology, research and practice 0 39644709
2022 Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct. Journal of human genetics 0 35087201

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