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FLASH GENE
Symbol SKP2 contributors: mct/pgu - updated : 22-02-2015
HGNC name S-phase kinase-associated protein 2 (p45)
HGNC id 10901
Location 5p13.2      Physical location : 36.152.188 - 36.184.145
Synonym name
  • CDK2/cyclin A-associated protein p45
  • F-box protein Skp2
  • F-box/LRR-repeat protein 1
  • Synonym symbol(s) FBL1, FBXL1, FLB1, MGC1366, p45skp2
    DNA
    TYPE functioning gene
    STRUCTURE 31.99 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • a functional E2F response element (hSRE2), not only participatingin activation of Skp2 promoter function during normal cell cycle progression into S phase, and also required for the high-level SKP2 gene expression in many tumor cell lines
  • NR4A3 transactivates the SP2 promoter through a nerve growth factor-induced clone B response element (NBRE) (is recruited to this NBRE site in the SKP2 promoter in response to mitogenic stimulation)
  • FOXO3 is found to be a transcriptional repressor of SKP2 gene expression by directly binding to the SKP2 promoter, thereby inhibiting SKP2 protein expression
  • MAPPING cloned Y linked N status provisional
    Physical map
    ADAMTS12 5q35 a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 12 SALPR 5p15.1-p14 G-protein coupled receptor SALPR MATP 5p13.3 membrane associated transporter protein AMACR 5p13.3-p12 alpha-methylacyl-CoA racemase C1QTNF3 5p13-p12 C1q and tumor necrosis factor related protein 3 LOC389280 5 similar to SMA3 protein LOC389281 5 similar to bA110H4.2 (similar to membrane protein) RAI14 5p13.3-p13.2 retinoic acid induced 14 FLJ25439 5p13.3 hypothetical protein FLJ25439 RAD1 5p13.3-p13.2 RAD1 homolog (S. pombe) BRIX 5p13.3 BRIX LOC134218 5p13.3 hypothetical protein LOC134218 AGXT2 5p13 alanine-glyoxylate aminotransferase 2 PRLR 5p14-p13.3 prolactin receptor LOC389282 5 similar to RIKEN cDNA C230086A09 gene FLJ23577 5p13.2 hypothetical protein FLJ23577 IL7R 5p13 interleukin 7 receptor MGC26610 5p13.2 hypothetical protein MGC26610 FLJ34658 5p13.2 hypothetical protein FLJ34658 LOC167127 5p13.2 hypothetical protein LOC167127 DKFZp434H2226 5p13.2 hypothetical protein DKFZp434H2226 SKP2 5p13 S-phase kinase-associated protein 2 (p45) FLJ30596 5p13.2 hypothetical protein FLJ30596 FLJ25422 5p13.2 hypothetical protein FLJ25422 SLC1A3 5p13 solute carrier family 1 (glial high affinity glutamate transporter), member 3 LOC345513 5p13.2 similar to Keratin, type I cytoskeletal 18 (Cytokeratin 18) (K18) (CK 18) IDN3 5p13.2 IDN3 protein LOC391777 5 similar to ribosomal protein S4, X-linked FLJ13231 5p13.2 hypothetical protein FLJ13231 LOC389283 5 LOC389283 OFD1P1 5p13 oral-facial-digital syndrome 1, pseudogene 1 NUP155 5p13 nucleoporin 155kDa FLJ10233 5p13.2 hypothetical protein FLJ10233 GDNF 5p13-p12 glial cell derived neurotrophic factor FLJ39155 5p13.2 hypothetical protein FLJ39155 LIFR 5p13-p12 leukemia inhibitory factor receptor
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 - 1600 47.6 424 - 1999 9858587
  • isoform 1
  • 10 - 1462 47.6 410 - 1999 9858587
  • isoform 2
  • 8 - 3273 - 210 - 1999 9858587
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Reproductivefemale systemplacenta  highly
    Respiratorylung    
    Urinarybladder   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  highly
    cell lineage
    cell lines highly, in many transformed cells
    fluid/secretion
    at STAGE
    cell cycle     cell cycle, interphase, S, checkpoint, G1S
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a F-box motif
  • a region with seven leucine rich repeats (LRR)
  • a C terminal domain interacting with substrates
  • HOMOLOGY
    Homologene
    FAMILY
  • F-box family
  • CATEGORY protooncogene
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    text
  • specific role to cytosolic SKP2 in the positive regulation of cell migration
  • acetylation of SKP2 in the nuclear localization signal (NLS) promotes its cytoplasmic retention, and cytoplasmic SKP2 enhances cellular migration through ubiquitination and destruction of CDH1
  • basic FUNCTION
  • plays a critical role in coordinating the G1/S transition and progression through the S phase of the cell cycle
  • substrate recognition subunit of SCF ubiquitin-protein ligase complex
  • controlling the binding of SKP1A/B to cyclin A/CDK2 complex
  • can inhibit the kinase activity of CCNA2-CDK2 both by direct inhibition of CCNA2-CDK2 and by inhibition of the activation of CDK2 by cyclin-dependent kinase (CDK)-activating kinase phosphorylation
  • controlling the abundance of the cyclin dependent kinase inhibitor CDKN1B by binding, leading to its ubiquitination, and inducing S phase in quiescent cells
  • inhibiting the tumor suppressor function of FOXO1
  • F-box component of an E3 ubiquitin ligase complex that targets CDKN1A and CCNE1 to the proteasome
  • regulates G2/M progression in a Tp53-dependent manner
  • regulates the antiproliferative function of the tumor suppressor RASSF1A via ubiquitin-mediated degradation at the G1-S transition
  • play a role in DNA repair and cell cycle regulation
  • F-box protein that forms the SCF complex with SKP1 and Cullin-1 to constitute an E3 ligase for ubiquitylation
  • SKP2B attenuates the activity of TP53 by inhibiting PHB
  • critical role in glucoincretin-induced beta-cell proliferation
  • regulate cellular proliferation by targeting several cell cycle-regulated proteins for ubiquitination and degradation, including cyclin-dependent kinase inhibitor CDKN1B
  • E3 ubiquitin ligase that affects cell cycle control and death, plays a critical role in the function of diabetogenic autoreactive pathogenic T cells (Tpaths) and regulatory T cells (Tregs)
  • important molecular mechanism mediating SKP2 function in balancing immune tolerance during autoimmune disease development
  • acetylation-dependent regulatory mechanism governing SKP2 oncogenic function, providing insight into how cytoplasmic SKP2 controls cellular migration
  • governs E-cadherin ubiquitination and degradation in the cytosol
  • key regulator in different cellular and molecular processes, through ubiquitin-proteasome degradation pathway
  • plays crucial roles in LAMTOR5-enhanced proliferation of breast cancer
  • may play a role in the development and progression of oral melanomas
  • CELLULAR PROCESS cell cycle, checkpoint
    cell cycle, progression
    protein, degradation
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • activation of the SKP2-CDKN1B pathway in response to mitogenic stimulation of vascular smooth muscle cells and during neointima formation is mediated at least in part by NR4A3
  • a component
  • complexing with SKP1, CUL1, CDC34 in the SCF complex
  • component of the SFC-SKP2 complex, with CKS1B
  • component of the E3 ubiquitin ligase SKP1-Cul1-Fbox complex
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with SKP1 (and binding the SCF constant catalytic core ubiquitin ligase)
  • binding to CKS1B, neccessary for binding to phosphorylated CDKN1B
  • interacting with FOXP3 (FOXP3 is a novel transcriptional repressor for the oncogene SKP2)
  • interacting with FOXO1 and promoting its degradation (reversed by proteasome inhibitors)
  • interacting with CDKN1B (interaction negatively regulated by TSC2)
  • target for E2F regulation that is disrupted in several tumor cell lines
  • interacting with CKS1B (binds to and activates cyclin-dependent kinases and also interacts with CKS1B to promote the ubiquitination and proteasomal degradation of CDKN1B)
  • interacts with Akt/protein kinase B (PKB)(directly phosphorylates SKP2, phosphorylation triggering SCF complex formation and E3 ligase activity)
  • interacting with VHL (destabilizes the F-box protein SKP2, a chief component of Skp, Cullin, F-box-containing complex that promotes DNA synthesis in the S phase)
  • is a direct transcriptional target for NR4A1
  • FOXO3 transcription factor is a novel and negative regulator of SKP2 SCF complex(
  • SKP2-mediatetd NBN ubiquitination is a vital event for ATM activation in response to DNA damage
  • existence of a novel cell cycle-associated, TADA3-regulated signaling pathway that promotes G1/S cell cycle progression by regulating CDKN1B stability through MYC-dependent control of SKP2 expression
  • SIRT3 tumor suppressor serves as the physiological deacetylase that antagonizes EP300-mediated SKP2 acetylation
  • LAMTOR5 was able to stimulate the promoter of SKP2 through binding to the -640/-443 region in SKP2 promoter involving activating E2F transcription factor 1 (E2F1)
  • SF3B3 overexpression reduces the binding of adaptor protein SKP1 and substrate receptor SKP2 to CUL1, whereas it has no effect on CAND1 binding to CUL1
  • LCK upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGFA expression, and suppressed cellular invasion
  • SKP2 may regulate CTNNB1 and its target gene expression to orchestrate hematopoietic stem cell (HSC) homing
  • MYCN bound directly to E-boxes within the SKP2 promoter and induced transcriptional activity which was decreased by the removal of MYCN and E-box mutation
  • cell & other
    REGULATION
    activated by BCR-ABL fusion oncogene frequently found in chronic myeloid leukemia (CML) cells can up-regulate SKP2 expression via transcriptional activation
    induced by Notch signaling (induces SKP2 expression and promotes reduction of CDKN1B in T-cell acute lymphoblastic leukemia cell lines)
    Other degradated by SCF ubiquitin ligase
    acetylated by EP300 at K68 and K71, which is a process that can be antagonized by the SIRT3 deacetylase
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in oral cancers and in high-grade lymphoma
    constitutional     --over  
    in mammalian cells causes a G1/S cell cycle arrest
    tumoral     --over  
    may overcome TP53-dependent cell cycle checkpoints in melanoma cells
    tumoral     --over  
    combination of high CCNE and SKP2 expression in breast cancer is associated with a poor prognosis and the basal phenotype
    tumoral     --other  
    cytoplasmic SKPp2 expression is associated with AKT1 and predicts poor prognosis in human breast carcinomas
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • could be useful as an immunohistochemical marker for differential diagnosis of oral benign and malignant melanocytic lesions
  • Therapy target therapeutic target in cancers with high levels of SKP2, through proteasome inhibitors
    SystemTypeDisorderPubmed
    cancer  
    therapeutic target in cancers with high levels of SKP2, through proteasome inhibitors
    cancerreproductivebreast
    cytoplasmic SKP2 may serve as a potential therapeutic target
    cancerbrainglioma/neuroblstoma
    SKP2 is a potential therapeutic target in non-MYCN amplified neuroblastoma
    ANIMAL & CELL MODELS