Affinage

MAPKAP1

Target of rapamycin complex 2 subunit MAPKAP1 · UniProt Q9BPZ7

Length
522 aa
Mass
59.1 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 25 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

MAPKAP1 (SIN1) is an essential scaffold subunit of mTORC2 that defines the complex's substrate specificity and couples it to upstream lipid and Ras signaling (PMID:16962653, PMID:17043309). Genetic ablation of SIN1 disrupts the rictor–mTOR interaction and abolishes Akt Ser473 (hydrophobic motif) phosphorylation while leaving Thr308 and mTORC1 outputs intact, establishing SIN1 as required for mTORC2 assembly and activity but dispensable for mTORC1 (PMID:16962653, PMID:17043309). The conserved central CRIM region adopts a ubiquitin-like fold that directly binds AGC-family substrate kinases including PKCε and SGK/Akt to recruit them for phosphorylation; SIN1 is dispensable for catalysis per se but essential for substrate selection, a function conserved from fission yeast to human (PMID:21806543, PMID:28264193). SIN1's C-terminal pleckstrin-homology domain binds the PI3K product PtdIns(3,4,5)P3 to drive mTORC2 membrane localization and activation, linking PI3K to mTORC2 (PMID:26526694), while its Raf-like Ras-binding domain engages activated H- and K-Ras and suppresses Ras-driven ERK signaling, with the PH domain inhibiting Ras–SIN1 binding (PMID:17303383, PMID:35522713). SIN1 activity is tuned by reciprocal phosphorylation: Akt phosphorylates SIN1 at T86 to create a positive feedback loop that amplifies mTORC2 activity and full Akt activation (PMID:26235620), whereas dual phosphorylation at T86 and T398 by Akt or S6K dissociates SIN1 from the complex as negative feedback, a control bypassed by the cancer-derived SIN1-R81T mutation that drives mTORC2 hyperactivation (PMID:24161930, PMID:24481632). Through these mechanisms SIN1-mTORC2 governs cell survival, lymphocyte development and metabolism, and tumor cell invasion (PMID:30428057, PMID:30705387, PMID:28692058). SIN1 additionally participates in mTORC2-independent activities, including a nuclear stress-response scaffolding role and regulation of cilia length (PMID:17054722, PMID:23727834).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 Medium

    Before SIN1's mammalian role was known, fission yeast work first placed it as a scaffold acting downstream of a stress MAP kinase rather than as an upstream activator, framing SIN1 as a specificity factor in signaling.

    Evidence sin1 deletion, two-hybrid, and transcription reporter assays in S. pombe

    PMID:10428959

    Open questions at the time
    • Did not connect SIN1 to TORC2 or to AGC-kinase phosphorylation
    • Mechanism of Atf1 stabilization not resolved
  2. 2006 High

    Established that SIN1 is an essential, mTORC2-specific subunit required for complex assembly and Akt Ser473 phosphorylation, defining its core function.

    Evidence sin1 knockout, reciprocal Co-IP, and in vivo/in vitro kinase assays in mammalian and Drosophila cells

    PMID:16962653 PMID:17043309

    Open questions at the time
    • Did not identify which SIN1 domain recruits substrates
    • Did not explain how SIN1 connects to upstream PI3K input
  3. 2007 Medium

    Identified SIN1's RBD and PH domains, revealing it binds activated Ras and antagonizes Ras-driven ERK, JNK and Akt signaling, expanding SIN1 beyond mTORC2.

    Evidence domain analysis, Co-IP, co-localization, siRNA and overexpression

    PMID:17303383

    Open questions at the time
    • Structural basis of Ras–SIN1 binding unresolved
    • Lipid specificity of the PH domain not defined
  4. 2008 Medium

    Showed SIN1 has cytoplasmic interactions beyond mTORC2 (PCBP2, IFNAR2, TNFα receptors) and is partitioned between nucleus and cytoplasm with rapamycin-sensitive dynamics, hinting at moonlighting and compartment-specific functions.

    Evidence two-hybrid, Co-IP, RNAi/apoptosis assays, and subcellular fractionation with rapamycin treatment

    PMID:18614546 PMID:18687895

    Open questions at the time
    • Functional significance of receptor associations not mechanistically resolved
    • How nuclear SIN1 differs from cytoplasmic mTORC2 SIN1 unclear
  5. 2011 High

    Defined SIN1's central conserved region as the adaptor that directly binds substrate kinase domains (PKCε, Akt), explaining how mTORC2 selects its substrates.

    Evidence Co-IP, domain mapping, dominant-negative SIN1 mutants, and in vitro kinase assays

    PMID:21806543

    Open questions at the time
    • Atomic structure of the substrate-binding region not yet determined
    • Whether binding mode is shared across all AGC substrates untested
  6. 2012 Medium

    Provided the first structural views of the SIN1 PH domain, predicting a phosphoinositide-binding site consistent with membrane targeting of TORC2.

    Evidence X-ray crystallography of human SIN1 and yeast Avo1 PH domains

    PMID:22505404

    Open questions at the time
    • Phosphoinositide binding not functionally validated in this study
    • Membrane recruitment not directly demonstrated structurally
  7. 2013 High

    Established phosphorylation of SIN1 (T86/T398) as a negative feedback switch that dissociates SIN1 from mTORC2, and linked a cancer-derived R81T mutation to escape from this control and mTORC2 hyperactivation.

    Evidence phospho-site mutagenesis, Co-IP, in vitro kinase assays, and patient-mutation analysis

    PMID:24161930 PMID:24481632

    Open questions at the time
    • Stoichiometry of dissociation in vivo not quantified
    • Phosphatase reversing these sites not identified
  8. 2013 Medium

    Revealed mTORC2-independent and stimulus-specific SIN1 functions: scaffolding ATF-2/p38 stress signaling, regulating cilia length via CCDC28B, coupling DNA-PKcs to UVB-induced Akt phosphorylation, and promoting EMT/invasion in HCC.

    Evidence Co-IP, RNAi, in vivo zebrafish/cell depletion, reporter and invasion assays across multiple studies

    PMID:17054722 PMID:23564492 PMID:23727834 PMID:24365180

    Open questions at the time
    • Whether these roles require or bypass the mTORC2 complex not fully resolved for each
    • Direct vs indirect nature of some interactions untested
  9. 2015 Medium

    Resolved the kinase identity for the activating feedback loop, showing Akt (not S6K) phosphorylates SIN1 T86 to amplify mTORC2 toward full Akt activation, and provided direct evidence the PH domain binds PtdIns(3,4,5)P3 to link PI3K to mTORC2.

    Evidence orthogonal pharmacological inhibition with phospho-specific antibodies; lipid-binding and membrane-localization data

    PMID:26235620 PMID:26526694

    Open questions at the time
    • Reconciliation of positive (Akt-T86) vs negative (T86/T398) feedback context-dependence incomplete
    • PI3K-link evidence cited via review commentary
  10. 2017 High

    Determined the SIN1 CRIM domain as a ubiquitin-like fold that confers substrate specificity rather than catalysis, and showed translational control of SIN1 by Pdcd4/eIF4A as a regulatory layer governing mTORC2 output and invasion.

    Evidence NMR structure with genetic rescue in fission yeast and mutagenesis; 5'UTR-luciferase reporter, Pdcd4 mutants, and silvestrol treatment

    PMID:28264193 PMID:28692058

    Open questions at the time
    • How CRIM discriminates among different AGC substrates not fully defined
    • In vivo relevance of Pdcd4–SIN1 translational axis beyond cell models untested
  11. 2019 Medium

    Placed SIN1-mTORC2 in physiological control of lymphocyte development and metabolism, identifying downstream effectors (PPAR-γ/PKM2, c-Myc stability) that connect the complex to glycolysis and growth.

    Evidence conditional SIN1 knockout in T and B lineages, flow cytometry, glycolysis and proliferation assays, pathway analysis

    PMID:22678916 PMID:30428057 PMID:30705387

    Open questions at the time
    • Direct biochemical link between SIN1 and PKM2/c-Myc not established
    • Tissue-specificity of effectors unclear
  12. 2022 High

    Provided atomic detail of the Ras–SIN1 RBD interface and showed the PH domain inhibits Ras binding, defining how SIN1 isoforms and conformations balance mTORC2 substrate activation against ERK suppression.

    Evidence X-ray crystallography of HRas/KRas–SIN1 RBD, interface mutagenesis, FRET competition, and SIN1 KO functional assays

    PMID:35522713

    Open questions at the time
    • How PH-mediated autoinhibition is regulated in cells not resolved
    • Physiological isoform that engages Ras most strongly not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIN1's multiple regulatory inputs — lipid binding, Ras engagement, dual feedback phosphorylation, isoform diversity, and translational control — are integrated to set mTORC2 activity in a context- and tissue-specific manner remains unresolved.
  • No unified structural model of full-length SIN1 within assembled mTORC2
  • Functional roles of most splice isoforms uncharacterized
  • Phosphatases and dissociation kinetics governing feedback not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2
Partners
AKT1CCDC28BHRASKRASMTORPCBP2PRKCERICTOR
Complex memberships
mTORC2

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SIN1/MIP1 (MAPKAP1) is an essential subunit of the mTORC2 (rictor-mTOR) complex. Genetic ablation of sin1 abolished Akt-Ser473 phosphorylation and disrupted rictor-mTOR interaction while maintaining Thr308 phosphorylation. Loss of Ser473 phosphorylation selectively affected FoxO1/3a but not TSC2, GSK3, S6K, or 4E-BP1, indicating SIN1-mTORC2 is required for cell survival but dispensable for mTORC1 function. Genetic ablation (sin1 knockout), immunoprecipitation, in vivo phosphorylation assays Cell High 16962653
2006 Sin1 is an essential component of mTORC2 but not mTORC1, required for mTORC2 complex formation, kinase activity toward Akt hydrophobic motif (Ser473), and Rictor-mTOR interaction. Sin1 knockdown decreases Akt phosphorylation in both Drosophila and mammalian cells. Disruption of Rictor in mice causes embryonic lethality and ablates Akt phosphorylation. RNAi knockdown in Drosophila and mammalian cells, Co-immunoprecipitation, in vitro kinase assay, Rictor knockout mice Genes & development High 17043309
2015 Akt (not S6K) is the major kinase responsible for phosphorylating SIN1 at T86 in all cell lines studied, creating a positive feedback loop: PDK1 phosphorylates Akt at T308 → Akt phosphorylates SIN1 at T86 → enhanced mTORC2 kinase activity → mTORC2 phosphorylates Akt at S473 for full Akt activation. Pharmacological inhibition of Akt, S6K, and mTOR; phospho-specific antibodies; multiple cell lines and conditions Cell reports High 26235620
2013 Phosphorylation of Sin1 at Thr86 and Thr398 by S6K or Akt (context-dependent) suppresses mTORC2 kinase activity by dissociating Sin1 from the mTORC2 complex, inhibiting Akt Ser473 phosphorylation. A cancer-patient-derived Sin1-R81T mutation impairs Sin1 T86 phosphorylation, leading to mTORC2 hyper-activation and enhanced Akt signaling. Phospho-site mutagenesis, Co-immunoprecipitation, in vitro kinase assay, patient-derived mutation analysis Nature cell biology High 24161930
2014 Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity by causing Sin1 dissociation from the holo-enzyme, reducing Akt activity and sensitizing cells to apoptosis. The ovarian cancer-derived Sin1-R81T mutation abolishes S6K-mediated T86 phosphorylation, bypassing this negative regulation. Phospho-site mutagenesis, Co-immunoprecipitation, apoptosis assays, cancer patient mutation analysis Protein & cell Medium 24481632
2011 The mTORC2 subunit Sin1 directly binds the PKCε kinase domain through Sin1's central conserved region, and serves as a selectivity adaptor for recruitment of mTORC2 substrates (both PKCε and PKB/Akt). Inducible expression of Sin1 mutants lacking the PKC-interaction domain disrupts PKC phosphorylation and suppresses PKB/Akt phosphorylation without affecting mTORC1 substrate p70S6K. Co-immunoprecipitation, domain mapping, inducible dominant-negative Sin1 mutant expression, in vitro kinase assay, 3D culture proliferation assay The Biochemical journal High 21806543
2017 The conserved region in the middle of Sin1 (Sin1CRIM) forms a ubiquitin-like fold domain that specifically binds TORC2 substrate kinases (e.g., Gad8/SGK) to recruit them for phosphorylation; Sin1 is dispensable for TORC2 catalytic activity per se but essential for substrate specificity. Sin1CRIM fused to a different TORC2 subunit can rescue substrate phosphorylation in sin1-null fission yeast. The substrate-recognition function is conserved in human Sin1CRIM. NMR solution structure determination, genetic rescue in sin1 null fission yeast, Co-immunoprecipitation, mutagenesis of acidic loop eLife High 28264193
2012 X-ray crystal structures of the C-terminal pleckstrin homology (PH) domain of S. cerevisiae Avo1 (Sin1 orthologue) and human Sin1 were determined, revealing a PH domain fold with a putative phosphoinositide binding site, consistent with membrane localization of TORC2. X-ray crystallography Acta crystallographica. Section F Medium 22505404
2015 The PH domain of SIN1 directly binds the PI3K lipid product PtdIns(3,4,5)P3 to promote mTORC2 kinase activation and membrane localization, providing a mechanistic link between PI3K and mTORC2. Lipid binding assay, membrane localization experiments (referenced review summarizing Liu et al. experimental findings) Cancer discovery Medium 26526694
2007 Human Sin1 contains a functional Raf-like Ras-binding domain (RBD) and a pleckstrin homology (PH) domain. The PH domain mediates lipid and membrane binding; the RBD binds activated H- and K-Ras. Sin1 and Ras co-immunoprecipitate and co-localize in vivo. Overexpression of Sin1 inhibits ERK, Akt, and JNK activation by Ras, while siRNA knockdown of Sin1 enhances Ras-induced ERK1/2 activation. Domain functional analysis, co-immunoprecipitation, co-localization imaging, siRNA knockdown, overexpression studies Cellular signalling Medium 17303383
2022 High-resolution crystal structures of HRas/KRas-SIN1 RBD complexes revealed the detailed interaction interface. Mutation of critical interface residues abolished Ras-SIN1 interaction. In SIN1 knockout cells, Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. The SIN1 PH domain has an inhibitory effect on Ras-SIN1 binding; a SIN1 isoform lacking the PH domain binds Ras more strongly. X-ray crystallography, site-directed mutagenesis, FRET competition assay, SIN1 knockout cell lines, kinase activity assays Proceedings of the National Academy of Sciences of the United States of America High 35522713
2008 SIN1 (MAPKAP1) interacts with poly(rC) binding protein 2 (PCBP2) through its N-terminal domain; PCBP2 and SIN1 can be co-immunoprecipitated together with the cytoplasmic domain of the IFN receptor IFNAR2 from HeLa cells. SIN1 also associates with TNFα receptors. RNAi silencing of either SIN1 or PCBP2 renders cells sensitive to basal and stress-induced apoptosis. Two-hybrid screen, co-immunoprecipitation, RNAi knockdown, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America Medium 18687895
2008 mTOR, mLST8, rictor, and Sin1 are less abundant in the nucleus than the cytoplasm of primary human fibroblasts. The mTOR/rictor complex is abundant in both compartments. Short-term rapamycin treatment triggers dephosphorylation of rictor and Sin1 exclusively in the cytoplasm without affecting mTORC2 assembly; prolonged rapamycin leads to complete dephosphorylation and cytoplasmic translocation of nuclear rictor and Sin1 accompanied by inhibition of mTORC2 assembly. Subcellular fractionation, immunofluorescence, Western blot, rapamycin treatment Human molecular genetics Medium 18614546
1999 Fission yeast Sin1 interacts with the Sty1/Spc1 SAPK MAP kinase. Cells lacking Sin1 display stress sensitivity and cell-cycle delay similar to sty1/spc1 deletion but Sin1 is not required for Sty1/Spc1 activation; rather Sin1 is required downstream for stress-dependent phosphorylation and stabilization of the transcription factor Atf1 and for transcription via the AP-1 factor Pap1. Genetic interaction (sin1 deletion), two-hybrid interaction, stress assays, kinase activity assays, transcription reporter assays, chimeric rescue constructs The EMBO journal Medium 10428959
2006 Mammalian Sin1 directly binds both ATF-2 and p38. Sin1 overexpression enhances osmotic stress-induced phosphorylation of ATF-2 and ATF-2-mediated transcription; siRNA knockdown of Sin1 suppresses these responses and inhibits osmotic stress-induced apoptosis and Gadd45β expression. Sin1 functions as a nuclear scaffold to promote ATF-2 signaling specificity under stress but not serum stimulation. Co-immunoprecipitation (direct binding), siRNA knockdown, overexpression, transcription reporter assay, apoptosis assay Genes to cells Medium 17054722
2013 SIN1 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial-mesenchymal transition (EMT); depletion of SIN1 significantly decreases invasion and migration of HCC cell lines. siRNA knockdown, invasion/migration assays, EMT marker analysis (Western blot, qPCR), immunohistochemistry Cancer Medium 23564492
2017 Tumor suppressor Pdcd4 inhibits Sin1 translation through an eIF4A-dependent mechanism acting on the SIN1 5'UTR. Loss of Pdcd4 increases Sin1 protein (not mRNA), enhancing mTORC2 activity and invasion. Pdcd4 mutants unable to bind eIF4A fail to inhibit Sin1 translation, mTORC2 activity, or invasion. Direct eIF4A inhibition with silvestrol suppresses Sin1 translation. 5'UTR-luciferase reporter assay, Pdcd4 knockdown/knockout/rescue, eIF4A binding mutants, silvestrol treatment, invasion assays Oncogene High 28692058
2013 DNA-PKcs associates with SIN1 in the cytosol upon UVB radiation in an EGFR-activation-dependent manner. This DNA-PKcs-SIN1 complexation is required for UVB-induced Akt Ser473 phosphorylation by mTORC2. Inhibition or depletion of either DNA-PKcs or SIN1 abolishes UVB-induced Akt Ser473 phosphorylation and enhances UVB-induced apoptosis. Co-immunoprecipitation, siRNA knockdown, dominant-negative kinase-dead mutation, gene depletion, EGFR inhibitor treatment, apoptosis assays Molecular cancer Medium 24365180
2013 CCDC28B interacts with SIN1 (a component of mTORC2) and this interaction is important both for mTOR signaling and for a mTORC-independent role of SIN1 in cilia length regulation. Depletion of CCDC28B reduces cilia length in vivo at least partly through its interaction with Sin1. Depletion of Rictor (another mTORC2 component) does not affect cilia length, indicating a specific Sin1 function independent of the full mTORC2 complex. Co-immunoprecipitation, in vivo zebrafish/cell depletion, cilia length measurement, Rictor vs Sin1 knockdown comparison Human molecular genetics Medium 23727834
2019 Sin1-mTORC2 controls early thymocyte (DN stage) development and glycolysis through an AKT-dependent PPAR-γ nuclear translocation pathway that controls PKM2 (pyruvate kinase M2) expression. Sin1 knockout in T lineage cells severely impairs DN thymocyte proliferation and glycolysis; PKM2 is identified as a novel Sin1 effector. Conditional Sin1 knockout in T cells, flow cytometry, glycolysis assays, PPAR-γ nuclear translocation analysis, PKM2 expression analysis Journal of molecular cell biology Medium 30428057
2019 Sin1-mTORC2 regulates B cell growth and metabolism by maintaining c-Myc protein stability and activating mTORC1 through Akt-dependent inactivation of GSK3 and TSC1/2. Genetic ablation of Sin1 in B cells reduces cell size, impairs metabolism, proliferation, antibody responses, and anti-viral immunity. B cell-specific Sin1 conditional knockout, flow cytometry, proliferation assays, mTORC1/2 pathway analysis, c-Myc stability assay Cellular & molecular immunology Medium 30705387
2012 Sin1 deficiency blocks mTORC2-dependent Akt phosphorylation in T cells. Sin1 is dispensable for T-cell receptor-induced growth, proliferation, and CD4+ helper cell differentiation, but Sin1 deficiency increases the proportion of Foxp3+ natural T-regulatory cells in the thymus. TGF-β-dependent Treg differentiation in vitro is enhanced by mTOR inhibition but not by loss of Sin1. Sin1 conditional knockout in hematopoietic system, flow cytometry, in vitro T cell differentiation assays, Akt phosphorylation analysis European journal of immunology Medium 22678916
2018 Sin1 T86 phosphorylation amplifies mTORC2-mediated downstream signals and is required for integrin αIIbβ3-mediated outside-in signaling in platelets, as well as hypoxia/ROS responses through the NAD+/Sirt3/SOD2 pathway. Platelet-specific Sin1 deficiency protects mice from ischemia-induced microvascular embolization and heart dysfunction after myocardial infarction. Platelet-specific Sin1 knockout mice, Sin1 T86 phosphorylation-deficient knockin mice, platelet activation assays, mouse myocardial infarction model Arteriosclerosis, thrombosis, and vascular biology Medium 30571167
2004 The human Sin1 gene (MAPKAP1) produces transcripts utilizing alternative polyadenylation signals and multiple splice variants that potentially encode functionally different isoforms. A highly conserved domain shared with S. pombe Sin1, Dictyostelium RIP3, and S. cerevisiae Avo1 was identified as defining the SIN1 orthologue family. Cloning and characterization of full-length human Sin1 mRNA, RT-PCR, sequence analysis Gene Low 15363842
2015 Sin1γ, a novel Sin1 isoform with a C-terminal truncation due to alternative 3' termination, can interact with mTORC2 components but its overexpression in Sin1-deficient MEFs has no significant impact on mTORC2 activity or subunit levels. Sin1γ localizes to a specific cytosolic location and its localization is transiently disrupted during the cell cycle. Isoform cloning, overexpression in Sin1-deficient MEFs, mTORC2 activity assay, subcellular localization imaging, cell cycle analysis PloS one Medium 26263164

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 1161 16962653
2006 Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes & development 411 17043309
2015 A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation. Cell reports 252 26235620
2013 Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nature cell biology 221 24161930
2013 Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells. Immunobiology 206 23735482
2008 Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Human molecular genetics 205 18614546
1995 Nitric oxide donor SIN-1 inhibits mammalian cardiac calcium current through cGMP-dependent protein kinase. The American journal of physiology 189 7530909
1991 A functional interaction between the C-terminal domain of RNA polymerase II and the negative regulator SIN1. Cell 164 2004420
1991 A negative regulator of HO transcription, SIN1 (SPT2), is a nonspecific DNA-binding protein related to HMG1. Molecular and cellular biology 154 2072912
2004 Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-kappaB in human gingival fibroblasts. Cytokine 129 15652448
2004 Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochemical and biophysical research communications 115 15485666
2018 Resveratrol inhibits pulmonary fibrosis by regulating miR-21 through MAPK/AP-1 pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 101 29843043
2007 Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling. Cellular signalling 91 17303383
2015 Interleukin-35 Inhibits Endothelial Cell Activation by Suppressing MAPK-AP-1 Pathway. The Journal of biological chemistry 90 26085094
2014 [6]-Gingerol induces caspase-dependent apoptosis and prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK/AP-1 signaling. PloS one 88 25157570
2005 MAPK/AP-1 signal pathway in tobacco smoke-induced cell proliferation and squamous metaplasia in the lungs of rats. Carcinogenesis 84 16051644
2016 Activation of Nrf2 Reduces UVA-Mediated MMP-1 Upregulation via MAPK/AP-1 Signaling Cascades: The Photoprotective Effects of Sulforaphane and Hispidulin. The Journal of pharmacology and experimental therapeutics 83 28011874
2004 Fluorescence measurements of steady state peroxynitrite production upon SIN-1 decomposition: NADH versus dihydrodichlorofluorescein and dihydrorhodamine 123. Journal of fluorescence 79 15622856
2006 Evidence that Spt2/Sin1, an HMG-like factor, plays roles in transcription elongation, chromatin structure, and genome stability in Saccharomyces cerevisiae. Molecular and cellular biology 75 16449659
2011 mTORC2 targets AGC kinases through Sin1-dependent recruitment. The Biochemical journal 73 21806543
2019 Impaired inflammasome activation and bacterial clearance in G6PD deficiency due to defective NOX/p38 MAPK/AP-1 redox signaling. Redox biology 65 31707353
2020 Syringaresinol Inhibits UVA-Induced MMP-1 Expression by Suppression of MAPK/AP-1 Signaling in HaCaT Keratinocytes and Human Dermal Fibroblasts. International journal of molecular sciences 61 32492931
2017 Tumor suppressor Pdcd4 attenuates Sin1 translation to inhibit invasion in colon carcinoma. Oncogene 60 28692058
2018 Rubus idaeus L. (red raspberry) blocks UVB-induced MMP production and promotes type I procollagen synthesis via inhibition of MAPK/AP-1, NF-κβ and stimulation of TGF-β/Smad, Nrf2 in normal human dermal fibroblasts. Journal of photochemistry and photobiology. B, Biology 59 29966991
2017 Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit. eLife 59 28264193
2009 The expression of the beta-defensins hBD-2 and hBD-3 is differentially regulated by NF-kappaB and MAPK/AP-1 pathways in an in vitro model of Candida esophagitis. BMC immunology 59 19523197
1999 Sin1: an evolutionarily conserved component of the eukaryotic SAPK pathway. The EMBO journal 58 10428959
2015 Glycyrrhetinic acid potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis. Expert opinion on therapeutic targets 57 25828376
2000 Effects of propofol on endothelial cells subjected to a peroxynitrite donor (SIN-1). Anaesthesia 57 11069332
2010 EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-kappaB in rat brain astrocytes. Journal of cellular physiology 55 20333648
1994 Role of the nitric oxide donor linsidomine chlorhydrate (SIN-1) in the diagnosis and treatment of erectile dysfunction. Urology 54 7941195
2016 Thymus vulgaris alleviates UVB irradiation induced skin damage via inhibition of MAPK/AP-1 and activation of Nrf2-ARE antioxidant system. Journal of cellular and molecular medicine 53 27641753
2013 DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-SIN1 association mediates ultraviolet B (UVB)-induced Akt Ser-473 phosphorylation and skin cell survival. Molecular cancer 53 24365180
1996 A precursor of the nitric oxide donor SIN-1 modulates the stress protein heme oxygenase-1 in rat liver. Biochemical and biophysical research communications 53 8769112
2008 Involvement of connexin 43 in angiotensin II-induced migration and proliferation of saphenous vein smooth muscle cells via the MAPK-AP-1 signaling pathway. Journal of molecular and cellular cardiology 52 18405916
2003 Grape and grape seed extract capacities at protecting LDL against oxidation generated by Cu2+, AAPH or SIN-1 and at decreasing superoxide THP-1 cell production. A comparison to other extracts or compounds. Free radical research 49 12797479
2015 The SIN1-PH Domain Connects mTORC2 to PI3K. Cancer discovery 46 26526694
2002 Genotoxicity, mitochondrial damage, and apoptosis in human lymphoblastoid cells exposed to peroxynitrite generated from SIN-1. Chemical research in toxicology 46 11952339
2019 Hydrangea serrata (Thunb.) Ser. Extract Attenuate UVB-Induced Photoaging through MAPK/AP-1 Inactivation in Human Skin Fibroblasts and Hairless Mice. Nutrients 42 30823635
2018 Paeonol extracted from Paeonia suffruticosa Andr. ameliorated UVB-induced skin photoaging via DLD/Nrf2/ARE and MAPK/AP-1 pathway. Phytotherapy research : PTR 40 29748977
1998 Neuronal death induced by SIN-1 in the presence of superoxide dismutase: protection by cyclic GMP. Neuropharmacology 40 9833636
2005 Alteration of cytosolic free calcium homeostasis by SIN-1: high sensitivity of L-type Ca2+ channels to extracellular oxidative/nitrosative stress in cerebellar granule cells. Journal of neurochemistry 38 15686499
2022 miR-1246-overexpressing exosomes suppress UVB-induced photoaging via regulation of TGF-β/Smad and attenuation of MAPK/AP-1 pathway. Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology 37 36114328
2014 Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity. Protein & cell 37 24481632
2022 Rosa davurica inhibits skin photoaging via regulating MAPK/AP-1, NF-κB, and Nrf2/HO-1 signaling in UVB-irradiated HaCaTs. Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology 36 36103110
2012 Neuroprotective effects of Cyperus rotundus on SIN-1 induced nitric oxide generation and protein nitration: ameliorative effect against apoptosis mediated neuronal cell damage. Neurotoxicology 36 23174672
2009 Role of MAPK/AP-1 signaling pathway in the protection of CEES-induced lung injury by antioxidant liposome. Toxicology 36 19464336
2001 Anti-adrenergic effects of nitric oxide donor SIN-1 in rat cardiac myocytes. American journal of physiology. Cell physiology 36 11401858
2022 Anti-Photoaging Effect of Hydrolysates from Pacific Whiting Skin via MAPK/AP-1, NF-κB, TGF-β/Smad, and Nrf-2/HO-1 Signaling Pathway in UVB-Induced Human Dermal Fibroblasts. Marine drugs 35 35621960
2018 MAPK/AP-1 pathway activation mediates AT1R upregulation and vascular endothelial cells dysfunction under PM2.5 exposure. Ecotoxicology and environmental safety 35 30529618
2013 SIN1 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial-mesenchymal transition. Cancer 35 23564492
2001 Induction of cyclo-oxygenase-2 in human endothelial cells by SIN-1 in the absence of prostaglandin production. British journal of pharmacology 33 11487528
2014 Ultraviolet A-induced cathepsin K expression is mediated via MAPK/AP-1 pathway in human dermal fibroblasts. PloS one 32 25048708
2010 cAMP-independent activation of protein kinase A by the peroxynitrite generator SIN-1 elicits positive inotropic effects in cardiomyocytes. Journal of molecular and cellular cardiology 32 20083118
2004 Alternative polyadenylation and splicing of mRNAs transcribed from the human Sin1 gene. Gene 32 15363842
2010 Cordycepin inhibits TPA-induced matrix metalloproteinase-9 expression by suppressing the MAPK/AP-1 pathway in MCF-7 human breast cancer cells. International journal of molecular medicine 31 20043135
2008 A link between SIN1 (MAPKAP1) and poly(rC) binding protein 2 (PCBP2) in counteracting environmental stress. Proceedings of the National Academy of Sciences of the United States of America 31 18687895
2001 SIN-1, a nitric oxide donor, ameliorates experimental allergic encephalomyelitis in Lewis rats in the incipient phase: the importance of the time window. Journal of immunology (Baltimore, Md. : 1950) 31 11313425
1996 Nitric oxide donor SIN-1 inhibits insulin release. The American journal of physiology 31 8897815
2015 The mucin MUC4 is a transcriptional and post-transcriptional target of K-ras oncogene in pancreatic cancer. Implication of MAPK/AP-1, NF-κB and RalB signaling pathways. Biochimica et biophysica acta 30 26477488
2013 The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex. Human molecular genetics 28 23727834
2002 Rhizobium sin-1 lipopolysaccharide (LPS) prevents enteric LPS-induced cytokine production. The Journal of biological chemistry 28 12193596
2020 Anticatabolic and Anti-Inflammatory Effects of Myricetin 3-O-β-d-Galactopyranoside in UVA-Irradiated Dermal Cells via Repression of MAPK/AP-1 and Activation of TGFβ/Smad. Molecules (Basel, Switzerland) 27 32183404
2019 Metabolic regulation of T cell development by Sin1-mTORC2 is mediated by pyruvate kinase M2. Journal of molecular cell biology 27 30428057
2012 Structures of the pleckstrin homology domain of Saccharomyces cerevisiae Avo1 and its human orthologue Sin1, an essential subunit of TOR complex 2. Acta crystallographica. Section F, Structural biology and crystallization communications 27 22505404
2020 Inhibitory effect of oyster hydrolysate on wrinkle formation against UVB irradiation in human dermal fibroblast via MAPK/AP-1 and TGFβ/Smad pathway. Journal of photochemistry and photobiology. B, Biology 26 32659645
2012 Cav1 suppresses tumor growth and metastasis in a murine model of cutaneous SCC through modulation of MAPK/AP-1 activation. The American journal of pathology 26 23267770
2008 Activation of MAPK/AP-1 signaling pathway in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard gas analog. Toxicology letters 26 18675330
2006 Dynorphin-mediated antinociceptive effects of L-arginine and SIN-1 (an NO donor) in mice. Brain research bulletin 26 16861110
2006 Sin1 binds to both ATF-2 and p38 and enhances ATF-2-dependent transcription in an SAPK signaling pathway. Genes to cells : devoted to molecular & cellular mechanisms 26 17054722
2023 Crosstalk between PD-L1 and Jak2-Stat3/ MAPK-AP1 signaling promotes oral cancer progression, invasion and therapy resistance. International immunopharmacology 25 37678027
2020 Concentrated growth factor inhibits UVA-induced photoaging in human dermal fibroblasts via the MAPK/AP-1 pathway. Bioscience reports 25 32627834
2019 Fibromodulin is upregulated by oxidative stress through the MAPK/AP-1 pathway to promote pancreatic stellate cell activation. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 25 31831391
2015 Characterization of Sin1 Isoforms Reveals an mTOR-Dependent and Independent Function of Sin1γ. PloS one 25 26263164
2012 Peroxynitrite donor SIN-1 alters high-affinity choline transporter activity by modifying its intracellular trafficking. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 22514319
1998 The C-terminal domain of Sin1 interacts with the SWI-SNF complex in yeast. Molecular and cellular biology 25 9632800
1995 Synergistic interaction of adenylate cyclase activators and nitric oxide donor SIN-1 on platelet cyclic AMP. European journal of pharmacology 25 7556414
2022 Structural insights into Ras regulation by SIN1. Proceedings of the National Academy of Sciences of the United States of America 23 35522713
2021 Acer tataricum subsp. ginnala Inhibits Skin Photoaging via Regulating MAPK/AP-1, NF-κB, and TGFβ/Smad Signaling in UVB-Irradiated Human Dermal Fibroblasts. Molecules (Basel, Switzerland) 23 33513930
2019 Sin1/mTORC2 regulate B cell growth and metabolism by activating mTORC1 and Myc. Cellular & molecular immunology 23 30705387
2016 Cigarette smoke extract-induced proliferation of normal human urothelial cells via the MAPK/AP-1 pathway. Oncology letters 23 28123584
2022 Attenuation of UV-induced skin photoaging in rats by walnut protein hydrolysates is linked to the modulation of MAPK/AP-1 and TGF-β/Smad signaling pathways. Food & function 21 34927661
2011 MAPK/AP-1 activation mediates TLR2 agonist-induced SPLUNC1 expression in human lung epithelial cells. Molecular immunology 21 21899893
2008 Hemin-H2O2-NO2(-) induced protein oxidation and tyrosine nitration are different from those of SIN-1: a study on glutamate dehydrogenase nitrative/oxidative modification. The international journal of biochemistry & cell biology 21 18835362
2002 X-linked Coffin-Lowry syndrome (CLS, MIM 303600, RPS6KA3 gene, protein product known under various names: pp90(rsk2), RSK2, ISPK, MAPKAP1). European journal of human genetics : EJHG 21 11896450
2001 Relaxation to authentic nitric oxide and SIN-1 in rat isolated mesenteric arteries: variable role for smooth muscle hyperpolarization. British journal of pharmacology 21 11429390
2023 MAPK/AP-1 Signaling Pathway Is Involved in the Protection Mechanism of Bone Marrow Mesenchymal Stem Cells-Derived Exosomes against Ultraviolet-Induced Photoaging in Human Dermal Fibroblasts. Skin pharmacology and physiology 20 36746125
2019 Agastache rugosa Kuntze Attenuates UVB-Induced Photoaging in Hairless Mice through the Regulation of MAPK/AP-1 and TGF-β/ Smad Pathways. Journal of microbiology and biotechnology 20 31474086
1993 Actions of 3-morpholinosydnonimin (SIN-1) on rabbit isolated penile erectile tissue. The Journal of urology 20 8396690
2023 Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling. Oncogene 19 37443304
2022 Dieckol Isolated from Eisenia bicyclis Ameliorates Wrinkling and Improves Skin Hydration via MAPK/AP-1 and TGF-β/Smad Signaling Pathways in UVB-Irradiated Hairless Mice. Marine drugs 19 36547926
2021 Santamarine Shows Anti-Photoaging Properties via Inhibition of MAPK/AP-1 and Stimulation of TGF-β/Smad Signaling in UVA-Irradiated HDFs. Molecules (Basel, Switzerland) 19 34208202
2019 Nitidine Chloride Inhibits SIN1 Expression in Osteosarcoma Cells. Molecular therapy oncolytics 19 30847386
2018 Helianthus annuus L. flower prevents UVB-induced photodamage in human dermal fibroblasts by regulating the MAPK/AP-1, NFAT, and Nrf2 signaling pathways. Journal of cellular biochemistry 19 30195253
2018 Sin1 (Stress-Activated Protein Kinase-Interacting Protein) Regulates Ischemia-Induced Microthrombosis Through Integrin αIIbβ3-Mediated Outside-In Signaling and Hypoxia Responses in Platelets. Arteriosclerosis, thrombosis, and vascular biology 19 30571167
2017 Pterocarpus santalinus L. Regulated Ultraviolet B Irradiation-induced Procollagen Reduction and Matrix Metalloproteinases Expression Through Activation of TGF-β/Smad and Inhibition of the MAPK/AP-1 Pathway in Normal Human Dermal Fibroblasts. Photochemistry and photobiology 19 28858391
2017 Refined Deep-Sea Water Suppresses Inflammatory Responses via the MAPK/AP-1 and NF-κB Signaling Pathway in LPS-Treated RAW 264.7 Macrophage Cells. International journal of molecular sciences 19 29088069
2016 Multiple Bcl-2 family immunomodulators from vaccinia virus regulate MAPK/AP-1 activation. The Journal of general virology 19 27312213
2003 Influence of the direct NO-donor SIN-1 on the interaction between platelets and stainless steel stents under dynamic conditions. Clinical hemorheology and microcirculation 19 12897410
2012 Sin1 regulates Treg-cell development but is not required for T-cell growth and proliferation. European journal of immunology 18 22678916

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