SKP2

Last updated
SKP2
Protein SKP2 PDB 1fqv.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SKP2 , FBL1, FBXL1, FLB1, p45, S-phase kinase-associated protein 2, E3 ubiquitin protein ligase, S-phase kinase associated protein 2
External IDs OMIM: 601436; MGI: 1351663; HomoloGene: 55942; GeneCards: SKP2; OMA:SKP2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6502

27401

Ensembl

ENSG00000145604

ENSMUSG00000054115

UniProt

Q13309

Q9Z0Z3

RefSeq (mRNA)

NM_001243120
NM_005983
NM_032637

NM_001285980
NM_013787
NM_145468

RefSeq (protein)

NP_001230049
NP_005974
NP_116026

NP_001272909
NP_038815

Location (UCSC) Chr 5: 36.15 – 36.2 Mb Chr 15: 9.11 – 9.16 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the SKP2 gene. [5] [6]

Contents

Structure and function

Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-140 position and the C-terminal region forming a concave surface consisting of ten leucine-rich repeats (LRRs). [7] The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which often—but not always—recognize substrates in a phosphorylation-dependent manner. In this SCF complex, Skp2 acts as the substrate recognition factor. [8] [9] [10]

F-box Domain

The F-box proteins are divided into three classes: Fbxws containing WD40 repeat domains, Fbxls containing leucine-rich repeats, and Fbxos containing either different protein–protein interaction modules or no recognizable motifs. [11] The protein encoded by this gene belongs to the Fbxls class. In addition to an F-box, this protein contains 10 tandem leucine-rich repeats. Alternative splicing of this gene generates 2 transcript variants encoding different isoforms. After the tenth LRR, the ~30-residue C-terminal tail turns back towards the first LRR, forming what has been referred to as a ‘safety-belt’ that might aid to pin down substrates into the concave surface formed by the LRRs. [12]

Skp2 forms a stable complex with the cyclin A-CDK2 S-phase kinase. It specifically recognizes and promotes the degradation of phosphorylated cyclin-dependent kinase inhibitor 1B (CDKN1B, also referred to as p27 or KIP1) predominantly in S, G2 phase, and the initial part of the M phase. [13] [14]

The degradation of p27 via Skp2 requires the accessory protein CKS1B. [15] [16] To prevent premature degradation of p27, Skp2 levels are kept low during early and mid-G1 due to the APC/CCdh1ubiquitin ligase, which mediates the ubiquitylation of Skp2. [17] [18]

Phosphorylation of Ser64 and, to a lesser extent, Ser72 of Skp2 contributes to the stabilization of Skp2 by preventing its association with APC/CCdh1; however, Skp2 phosphorylation on these residues is dispensable for its subcellular localization and for Skp2 assembly into an active SCF ubiquitin ligase. [19] [20] [21] [22] [23]

Role in cell cycle regulation

Progression through the cell cycle is tightly regulated by cyclin-dependent kinases (CDKs), and their interactions with cyclins and CDK inhibitors (CKIs). Relative amounts of these signals oscillate during each stage of the cell cycle due to periodic proteolysis; [24] the ubiquitin-proteasome system mediates the degradation of these mitotic regulatory proteins, controlling their intracellular concentrations. [25] [26] These and other proteins are recognized and degraded by the proteasome from the sequential action of three enzymes: E1 (ubiquitin-activating enzyme), one of many E2s (ubiquitin-conjugating enzyme), and one of many E3 ubiquitin ligase. [27] The specificity of ubiquitination is provided by the E3 ligases; these ligases physically interact with the target substrates. Skp2 is the substrate recruiting component of the SCFSkp2 complex, which targets cell cycle control elements, such as p27 and p21. [28] [29] [30] Here, SKP2 has been implicated in double negative feedback loops with both p21 and p27, that control cell cycle entry and G1/S transition. [31] [32]

Clinical significance

Skp2 behaves as an oncogene in cell systems [33] and is an established protooncogene causally involved in the pathogenesis of lymphomas. [34] One of the most critical CDK inhibitors involved in cancer pathogenesis is p27Kip1, which is involved primarily in inhibiting cyclin E-CDK2 complexes (and to a lesser extent cyclin D-CDK4 complexes). [35] Levels of p27Kip1 (like all other CKIs) rise and fall in cells as they either exit or re-enter the cell cycle, these levels are not modulated at the transcriptional level, but by the actions of the SCFSkp2 complex in recognizing p27Kip1 and tagging it for destruction in the proteasome system. [24] It has been shown that as cells enter G0 phase, reducing levels of Skp2 explain the increase in p27Kip1, creating an apparent inverse relationship between Skp2 and p27Kip1. [17] Robust evidence has been amassed that strongly suggests Skp2 plays an important role in cancer and is also involved in cancer-associated drug resistance. [36]

Overexpression

Overexpression of Skp2 is frequently observed in human cancer progression and metastasis, and evidence suggests that Skp2 plays a proto-oncogenic role both in vitro and in vivo. [8] Skp2 overexpression has been seen in: lymphomas, [37] prostate cancer, [38] melanoma, [39] nasopharyngeal carcinoma, [40] [41] pancreatic cancer, [42] and breast carcinomas. [43] [44] Additionally, overexpression of Skp2 is correlated with a poor prognosis in breast cancer. [45] [46] As one would expect, Skp2 overexpression promotes growth and tumorigenesis in a xenograft tumor model. [47] By extension of this fact, Skp2 inactivation profoundly restricts cancer development by triggering a massive cellular senescence and/or apoptosis response that is surprisingly observed only in oncogenic conditions in vivo. [48] This response is triggered in a p19Arf/p53-independent, but p27-dependent manner. [48]

Using a Skp2 knockout mouse model, multiple groups have shown Skp2 is required for cancer development in different conditions of tumor promotion, including PTEN, ARF, pRB inactivation as well as Her2/Neu overexpression. [49]

Genetic approaches have demonstrated that Skp2 deficiency inhibits cancer development in multiple mouse models by inducing p53-independent cellular senescence and blocking Akt-mediated aerobic glycolysis. Akt activation by Skp2 is linked to aerobic glycolysis, as Skp2 deficiency impairs Akt activation, Glut1 expression, and glucose uptake thereby promoting cancer development. [50]

Potential use as a clinical target

Skp2 is of considerable interest as a novel and attractive target for cancer therapeutical development, as disrupting the SCF complex will result in increased levels of p27, which will inhibit aberrant cellular proliferation. Although Skp2 is an enzyme, its function requires the assembly of the other members of the SCF complex. As Skp2 is the rate-limiting component of the SCF complex, effective inhibitors should be focused on the interfaces of Skp2 with the other members of the SCF complex, which is much more difficult than traditional enzyme inhibition. Small molecule inhibitors of the binding site between Skp2 and its substrate p27 have been discovered, and these inhibitors induce p27 accumulation in a Skp2-dependent manner and promote cell cycle arrest. [51] Another recent discovery were inhibitors of the Skp1/Skp2 interface that resulted in: restoring p27 levels, suppressing survival, trigger p53-independent senescence, exhibit potent antitumor activity in multiple animal models, and were also found to affect Akt-mediated glycolysis. [52] Skp2 is a potential target for pten-deficient cancers. [48]

Interactions

SKP2 has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

p21 Protein

p21Cip1, also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.

<span class="mw-page-title-main">SCF complex</span>

Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

<span class="mw-page-title-main">F-box protein</span> Protein containing at least one F-box domain

F-box proteins are proteins containing at least one F-box domain. The first identified F-box protein is one of three components of the SCF complex, which mediates ubiquitination of proteins targeted for degradation by the 26S proteasome.

<span class="mw-page-title-main">Cyclin-dependent kinase 2</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

<span class="mw-page-title-main">CDKN1B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

<span class="mw-page-title-main">CUL1</span> Protein-coding gene in humans

Cullin 1, also known as CUL1, is a human protein and gene from cullin family. This protein plays an important role in protein degradation and protein ubiquitination.

<span class="mw-page-title-main">RBX1</span> Protein-coding gene in the species Homo sapiens

RING-box protein 1 is a protein that in humans is encoded by the RBX1 gene.

<span class="mw-page-title-main">BTRC (gene)</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">COP9 constitutive photomorphogenic homolog subunit 5</span> Protein-coding gene in the species Homo sapiens

COP9 constitutive photomorphogenic homolog subunit 5 (Arabidopsis), also known as COPS5 or Csn5, is a gene conserved from humans to Saccharomyces cerevisiae.

<span class="mw-page-title-main">FBXW7</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 7 is a protein that in humans is encoded by the FBXW7 gene.

<span class="mw-page-title-main">CDC34</span> Protein-coding gene in the species Homo sapiens

CDC34 is a gene that in humans encodes the protein Ubiquitin-conjugating enzyme E2 R1. This protein is a member of the ubiquitin-conjugating enzyme family, which catalyzes the covalent attachment of ubiquitin to other proteins.

<span class="mw-page-title-main">FBXO5</span> Protein-coding gene in the species Homo sapiens

F-box only protein 5 is a protein that in humans is encoded by the FBXO5 gene.

<span class="mw-page-title-main">CKS1B</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.

<span class="mw-page-title-main">FBXW11</span> Protein-coding gene in the species Homo sapiens

βTrCP2 is a protein that in humans is encoded by the FBXW11 gene.

<span class="mw-page-title-main">FBXL2</span> Gene of the species Homo sapiens

F-box/LRR-repeat protein 2 is a protein that in humans is encoded by the FBXL2 gene.

<span class="mw-page-title-main">CCNF</span> Protein-coding gene in humans

G2/mitotic-specific cyclin-F is a protein that in humans is encoded by the CCNF gene.

<span class="mw-page-title-main">Cullin</span> Hydrophobic scaffold protein

Cullins are a family of hydrophobic scaffold proteins which provide support for ubiquitin ligases (E3). All eukaryotes appear to have cullins. They combine with RING proteins to form Cullin-RING ubiquitin ligases (CRLs) that are highly diverse and play a role in myriad cellular processes, most notably protein degradation by ubiquitination.

Sic1, a protein, is a stoichiometric inhibitor of Cdk1-Clb complexes in the budding yeast Saccharomyces cerevisiae. Because B-type cyclin-Cdk1 complexes are the drivers of S-phase initiation, Sic1 prevents premature S-phase entry. Multisite phosphorylation of Sic1 is thought to time Sic1 ubiquitination and destruction, and by extension, the timing of S-phase entry.

<span class="mw-page-title-main">S-phase kinase-associated protein 1</span> Protein-coding gene in the species Homo sapiens

S-phase kinase-associated protein 1 is an enzyme that in humans is encoded by the SKP1 gene.

References

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