ReviewCancer

Degrons in cancer

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaak9982
DOI: 10.1126/scisignal.aak9982
  • Fig. 1 The steps to 26S proteasome-mediated degradation.

    (Top) The overall process by which ubiquitin (Ub) is transferred to substrate proteins. (Middle) Mechanism of transfer for the different families of E3 ligases and E3 ligase complexes. HECT domain–containing E3 ligases form an intermediate bond with the ubiquitin, whereas RING domain–containing E3 ligases, in general, provide a platform for the direct transfer of ubiquitin to the substrate, with the exception of RBR E3 ligases, which may form intermediate bonds like the HECT-type E3 ligases (359). Some RING-type E3 ligases can function individually; some ligases function as part of protein complexes, such as Cullin-RING E3 ligase (CRL) complexes or anaphase-promoting complex/cyclosome (APC/C). Apart from the RING domain–bearing subunit, E3 ligase complexes may include additional subunits such as adaptor proteins, scaffold proteins, substrate receptor proteins, and accessory proteins. (Bottom) Degradation of polyubiquitinated substrates by the 26S proteasome in an energy-dependent reaction. The ubiquitin moieties attached to the substrate are recycled. AMP, adenosine 5′-monophosphate; PPi, inorganic pyrophosphate; Pi, inorganic phosphate.

  • Fig. 2 Classification of E3 ligase proteins and complexes.

    Representative examples of the main families of E3 ligases are shown. A subset of the possible substrate receptor subunits for the Cullin-RING E3 ligase complexes is shown beneath each complex.

  • Fig. 3 E3 ligase–degron complexes.

    (A) p53-MDM2, the p53 degron peptide enters a deep hydrophobic pocket on MDM2. The three key hydrophobic residues from p53 peptide are shown [Protein Data Bank (PDB): 1YCR]. (B) Structure of SKP1-SKP2-CKS1 in complex with the p27KIP1 phosphodegron peptide. SKP2 is rendered in gray surface, whereas CKS1 is represented in dark gray surface, with red (oxygen) and blue (nitrogen) polar functional groups. The small peptide from the p27KIP1 is rendered in ribbon representation with purple color: Its phosphothreonine interacts with positively charged CKS1 surface (blue region), which provides the phosphospecificity. SKP1 is not shown for clarity (PDB: 2AST). (C) Doubly phosphorylated β-catenin degron motif (see Table 1) in complex with β-TrCP1 and SKP1. Both of these molecules are shown in gray surface representation, whereas the β-catenin fragment is rendered as purple ribbon (PDB: 1P22). (D) COP1 E3 ligase with TRB1 degron. TRB1 binds on the conserved surface of COP1 in an extended manner. COP1 with WD40 repeats (β-propellers) is rendered as ribbon, whereas TRB1 peptide is rendered in stick representation and colored purple. (PDB: 5IGQ). Interchain H bonds are represented in magenta. Motif-defining positions have been rendered as yellow sticks for all the cases.

  • Fig. 4 Selected functional elements in four regulatory proteins with modular architectures and well-studied degrons.

    Only the DNA binding domains (DBD; in black) of p53 and ETV1 are natively folded; the remaining parts of these proteins are intrinsically unstructured, with larger functional regions indicated in light blue. The sites of degrons are indicated with red arrows and labeled with the cognate E3 ligase. The degrons recognized by FBXW7 and SKP2-CKS1 must be phosphorylated. Phosphorylation of or near the degrons recognized by ITCH and MDM2 abrogates recognition. Other classes of linear motif are shown as light brown rectangles, and phosphorylation sites are shown as circles. TAD, transactivation domain; 4X, tetramerization domain; NLS, nuclear localization signal; NES, nuclear export signal; USP7 dock, USP7 binding motif; bZIP, basic leucine zipper (coiled coil) dimerization and DNA binding domain; ETS DBD, DNA binding domain found in ETS-like transcription factors; TMPRSS2-ETV1 fusion, site of cancer gene fusion event that has deleted the ETV1 N-terminal degron; iCyc-CDK, inhibitory module that binds across the cyclin-CDK dimer; Cyclin box, docking motif that mediates binding to cyclins.

  • Fig. 5 Positional density of degrons in protein sequences.

    The plot shows the relative density of degron locations in protein sequences. All protein sequences that contain at least one degron (166 proteins from table S1 and http://dosztanyi.web.elte.hu/CANCER/DEGRON/TP.html) were split into 100 equal bins. The bins were numbered from 1 to 100 in the direction of N terminus to C terminus of the protein sequence. The number of degrons overlapping each bin was counted, and a density diagram was generated using ggplot2 geom_density function (360).

  • Fig. 6 Cell cycle phase diagram showing where degrons function in the cycle.

    Degron-containing protein names are categorized adjacent to the cell cycle phase during which the degradation of the protein enables progression of the cell cycle.

  • Fig. 7 Cancer-promoting mechanisms of impaired protein degradation.

    Cellular abundance of proteins can be deregulated because of genetic mutations that lead to loss of binding to the E3 ligase or substrate receptor of an E3 ligase complex. Partial or complete loss of the degron-containing region of a protein or mutations in the degron recognition surface of an E3 ligase (or complex) may impair binding to the target substrate. If the target substrate is an oncoprotein, accumulation of such a protein can have a tumorigenic effect. Alternatively, cellular abundance of proteins can be deregulated because of anomalies in the expression patterns of the E3 ligases or E3 ligase complexes that tag the substrate proteins for 26S proteasomal degradation. In the absence of mutations in either the E3 ligase or the substrate degron, down-regulation of an E3 ligase (or complex) that targets an oncoprotein or the up-regulation of an E3 ligase that targets a tumor suppressor could have a similar cancer-promoting impact on the cell.

  • Fig. 8 Complexes of docked drugs.

    (A) Proteasome:bortezomib (whole proteasome and outtake box of the bound bortezomib). The structured is rendered using PDB: 5LF3. Inset shows drug in binding pocket of one of the proteasome subunit (H bonds colored magenta). Proteasome surface of α subunits is colored in different shades of blue, whereas surface corresponding to β subunits is colored gray. (B) MDM2–Nutlin-3A structure (nutlin molecule is drawn in stick and MDM2 in surface representation). Binding of Nutlin-3A on MDM2 blocks degron interaction interface on it. (C) Thalidomide (analog)–lenalidomide in complex with cereblon. Lenalidomide (represented in stick with cyan color) is bound in the deep hydrophobic pocket on cereblon (surface representation in gray). (D) Lenalidomide in complex with cereblon creates a novel binding surface for CK1α (ribbon colored green). The loop from CK1α can be seen interacting with the surface on cereblon. Inset with zoomed-in drug (stick representation, colored cyan with mesh over it) shows the interactions on the cereblon where it is surrounded by tryptophans (stick representation in gray).

  • Table 1 Degron motifs and cancer-associated dysfunction.
    Gene
    name
    Protein
    name
    E3 ligase or subunit-
    recognizing degron
    InstanceStarting
    position
    Motif*SourceAssociated mechanism in cancer
    TP53p53MDM2FSDLWKLL19F[^P]{3}W[^P]{2,3}
    [VIL]
    DEG_MDM2_1Increased degradation
    by increased E3
    ligase activity
    CDKN1Bp27KIP1SKP2-CKS1SVEQTPKK183..[DE].(T)P.KDEG_SCF_SKP2-
    CKS1_1
    Increased degradation
    by increased E3
    ligase activity
    CTNNB1β-cateninβ-TrCP1DSGIHS32D(S)G.{2,3}([ST])DEG_SCF_TRCP1_1Missense mutations
    in degron
    MYCMYCFBXW7LLPTPPLS55[LIVMP].{0,2}(T)P..
    ([ST])
    DEG_SCF_FBW7_1Translocation, mutation of the
    posttranslational modification site
    needed for E3 ligase binding,
    increased gene expression,
    and stabilization by MCV-mediated
    inhibition of FBWX7
    ERGERGSPOPASSSS42[AVP].[ST][ST][ST](61)Gene deletion by chromosomal
    translocation
    HIF1AHIF-1αVHLLAPAAGDTIISLDF400[IL]A(P).{6,8}
    [FLIVM].[FLIVM]
    DEG_ODPH_VHL_1Stabilization by E3 ligase
    inactivation
    NOTCH1NOTCH1FBXW7PFLTPSPE2508[LIVMP].{0,2}(T)P..EDEG_SCF_FBW7_2Truncating mutations in C-terminal
    PEST region
    TP63p63ITCHPPPY540PP.Y(342)Reduced gene
    expression
    NFE2L2NRF2KEAP1DEETGE77[DNS].[DES][TNS]
    GE
    DEG_Kelch_Keap1_1Missense mutations in both
    degrons, NRF2 deletion induces
    tumor formation
    NFE2L2NRF2KEAP1QDIDLGV26QD.DLGVDEG_Kelch_Keap1_2
    ETV1ETV1COP1DEQFVPDY67[STDE]{1,3}.{0,2}
    [TSDE].{2,3}
    VP[STDE]G{0,1}
    [FLIMVYPA]
    DEG_COP1Translocation deleting
    the N-terminal degron
    CSF1RCSF-1RCBLLLQPNNYQFC963[DN].(Y)[ST]..P(157)Mutations abolishing posttranslational
    modification site needed for E3
    ligase binding
    METc-Met
    (HGFR)
    CBLDYR1002D(Y)R(157)Mutations in posttranslational
    modification site needed for E3 ligase
    binding/exon skipping/translocation
    deleting the degron
    SH2BAPSCBLRAVENQYSFY623RA[VI].NQ(Y)[ST](157)
    AURKBAurora
    kinase B
    CDH1QKENS3.KEN.DEG_APCC_KENBOX_2
    CCNA1Cyclin A1CDC20/CDH1FDIYMD135[ILVMF].[ILMVP]
    [FHY].[DE]
    LIG_APCC_ABBA_1
    CCNB1Cyclin B1CDC20/CDH1PRTALGDIG41.R..L..[LIVM].DEG_APCC_DBOX_1
    PTTG1SecurinCDC20DKENG8.KEN.DEG_APCC_KENBOX_2

    *Definition of regular expressions describing linear motif sequence conservation: [LIV], [] refers to group of amino acids, in this case, Leu, Ile, and Val are all allowed; [^P], anything but Pro is allowed; a period (.) denotes any kind of residue; (T), modified residue (that is, phosphorylated Thr); .{0.2}, variable length position, in this case, 0, 1, and 2 positions of any kind of amino acid.

    †Known motifs are represented as standard regular expressions and were taken from the ELM database (48) or from the references cited.

    ‡Does not meet standard motif definition.

    Supplementary Materials

    • Supplementary Materials for:

      Degrons in cancer

      Bálint Mészáros, Manjeet Kumar, Toby J. Gibson,* Bora Uyar, Zsuzsanna Dosztányi*

      *Corresponding author. Email: dosztanyi{at}caesar.elte.hu (Z.D.); toby.gibson{at}embl.de (T.J.G.)

      This PDF file includes:

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      Other Supplementary Material for this manuscript includes the following:

      • Table S1 (.Microsoft Excel format). List of known degron motifs.
      • Table S2 (.Microsoft Excel format). List of E3 target recognition subunits.
      • Additional information can be found at http://dosztanyi.web.elte.hu/CANCER/DEGRON/.

      [Download Tables S1 and S2]


      Citation: B. Mészáros, M. Kumar, T. J. Gibson, B. Uyar, Z. Dosztányi, Degrons in cancer. Sci. Signal. 10, eaak9982 (2017).

      © 2017 American Association for the Advancement of Science