SKP2

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).{{cite journal | vauthors = Bai C, Sen P, Hofmann K, Ma L, Goebl M, Harper JW, Elledge SJ | title = SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box | journal = Cell | volume = 86 | issue = 2 | pages = 263–74 | date = July 1996 | pmid = 8706131 | doi = 10.1016/S0092-8674(00)80098-7 | s2cid = 18387009 | doi-access = free }} 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.{{cite journal | vauthors = Chan CH, Lee SW, Wang J, Lin HK | title = Regulation of Skp2 expression and activity and its role in cancer progression | journal = TheScientificWorldJournal | volume = 10 | pages = 1001–15 | year = 2010 | pmid = 20526532 | pmc = 5763972 | doi = 10.1100/tsw.2010.89 | doi-access = free }}{{cite journal | vauthors = Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP | title = Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex | journal = Nature | volume = 416 | issue = 6882 | pages = 703–9 | date = April 2002 | pmid = 11961546 | doi = 10.1038/416703a | bibcode = 2002Natur.416..703Z | s2cid = 4423882 }}{{cite journal | vauthors = Nakayama KI, Nakayama K | title = Regulation of the cell cycle by SCF-type ubiquitin ligases | journal = Seminars in Cell & Developmental Biology | volume = 16 | issue = 3 | pages = 323–33 | date = June 2005 | pmid = 15840441 | doi = 10.1016/j.semcdb.2005.02.010 }}

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.{{cite journal | vauthors = Kipreos ET, Pagano M | title = The F-box protein family | journal = Genome Biology | volume = 1 | issue = 5 | pages = REVIEWS3002 | year = 2000 | pmid = 11178263 | pmc = 138887 | doi = 10.1186/gb-2000-1-5-reviews3002 | doi-access = free }} 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.{{cite journal | vauthors = Cardozo T, Pagano M | title = The SCF ubiquitin ligase: insights into a molecular machine | journal = Nature Reviews Molecular Cell Biology | volume = 5 | issue = 9 | pages = 739–51 | date = September 2004 | pmid = 15340381 | doi = 10.1038/nrm1471 | s2cid = 11118665 }}

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.{{cite journal | vauthors = Carrano AC, Eytan E, Hershko A, Pagano M | title = SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 | journal = Nature Cell Biology | volume = 1 | issue = 4 | pages = 193–9 | date = August 1999 | pmid = 10559916 | doi = 10.1038/12013 | s2cid = 20634301 }}{{cite journal | vauthors = Tsvetkov LM, Yeh KH, Lee SJ, Sun H, Zhang H | title = p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27 | journal = Current Biology | volume = 9 | issue = 12 | pages = 661–4 | date = June 1999 | pmid = 10375532 | doi = 10.1016/S0960-9822(99)80290-5 | s2cid = 16110715 | doi-access = free }}

The degradation of p27 via Skp2 requires the accessory protein CKS1B.{{cite journal | vauthors = Sitry D, Seeliger MA, Ko TK, Ganoth D, Breward SE, Itzhaki LS, Pagano M, Hershko A | title = Three different binding sites of Cks1 are required for p27-ubiquitin ligation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 44 | pages = 42233–40 | date = November 2002 | pmid = 12140288 | doi = 10.1074/jbc.M205254200 | doi-access = free }}{{cite journal | vauthors = Ganoth D, Bornstein G, Ko TK, Larsen B, Tyers M, Pagano M, Hershko A | title = The cell-cycle regulatory protein Cks1 is required for SCF(Skp2)-mediated ubiquitinylation of p27 | journal = Nature Cell Biology | volume = 3 | issue = 3 | pages = 321–4 | date = March 2001 | pmid = 11231585 | doi = 10.1038/35060126 | s2cid = 9638655 }} To prevent premature degradation of p27, Skp2 levels are kept low during early and mid-G1 due to the APC/C^Cdh1ubiquitin ligase, which mediates the ubiquitylation of Skp2.{{cite journal | vauthors = Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M | title = Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase | journal = Nature | volume = 428 | issue = 6979 | pages = 190–3 | date = March 2004 | pmid = 15014502 | doi = 10.1038/nature02330 | s2cid = 4401971 }}{{cite journal | vauthors = Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG | title = Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex | journal = Nature | volume = 428 | issue = 6979 | pages = 194–8 | date = March 2004 | pmid = 15014503 | doi = 10.1038/nature02381 | bibcode = 2004Natur.428..194W | s2cid = 4418103 }}

Phosphorylation of Ser64 and, to a lesser extent, Ser72 of Skp2 contributes to the stabilization of Skp2 by preventing its association with APC/C^Cdh1; however, Skp2 phosphorylation on these residues is dispensable for its subcellular localization and for Skp2 assembly into an active SCF ubiquitin ligase.{{cite journal | vauthors = Rodier G, Coulombe P, Tanguay PL, Boutonnet C, Meloche S | title = Phosphorylation of Skp2 regulated by CDK2 and Cdc14B protects it from degradation by APC(Cdh1) in G1 phase | journal = The EMBO Journal | volume = 27 | issue = 4 | pages = 679–91 | date = February 2008 | pmid = 18239684 | pmc = 2262036 | doi = 10.1038/emboj.2008.6 }}{{cite journal | vauthors = Bashir T, Pagan JK, Busino L, Pagano M | title = Phosphorylation of Ser72 is dispensable for Skp2 assembly into an active SCF ubiquitin ligase and its subcellular localization | journal = Cell Cycle | volume = 9 | issue = 5 | pages = 971–4 | date = March 2010 | pmid = 20160477 | doi = 10.4161/cc.9.5.10914 | pmc = 3827631 }}{{cite journal | vauthors = Boutonnet C, Tanguay PL, Julien C, Rodier G, Coulombe P, Meloche S | title = Phosphorylation of Ser72 does not regulate the ubiquitin ligase activity and subcellular localization of Skp2 | journal = Cell Cycle | volume = 9 | issue = 5 | pages = 975–9 | date = March 2010 | pmid = 20160482 | doi = 10.4161/cc.9.5.10915 | doi-access = free }}{{cite journal | vauthors = Gao D, Inuzuka H, Tseng A, Chin RY, Toker A, Wei W | title = Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction | journal = Nature Cell Biology | volume = 11 | issue = 4 | pages = 397–408 | date = April 2009 | pmid = 19270695 | pmc = 2910589 | doi = 10.1038/ncb1847 }}{{cite journal | vauthors = Wang H, Cui J, Bauzon F, Zhu L | title = A comparison between Skp2 and FOXO1 for their cytoplasmic localization by Akt1 | journal = Cell Cycle | volume = 9 | issue = 5 | pages = 1021–2 | date = March 2010 | pmid = 20160512 | pmc = 2990537 | doi = 10.4161/cc.9.5.10916 }}

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;{{cite journal | vauthors = Murray AW | title = Recycling the cell cycle: cyclins revisited | journal = Cell | volume = 116 | issue = 2 | pages = 221–34 | date = January 2004 | pmid = 14744433 | doi = 10.1016/S0092-8674(03)01080-8 | s2cid = 1614485 | doi-access = free }} the ubiquitin-proteasome system mediates the degradation of these mitotic regulatory proteins, controlling their intracellular concentrations.{{cite journal | vauthors = Weissman AM | title = Themes and variations on ubiquitylation | journal = Nature Reviews Molecular Cell Biology | volume = 2 | issue = 3 | pages = 169–78 | date = March 2001 | pmid = 11265246 | doi = 10.1038/35056563 | s2cid = 20387846 }}{{cite journal | vauthors = Pickart CM | title = Back to the future with ubiquitin | journal = Cell | volume = 116 | issue = 2 | pages = 181–90 | date = January 2004 | pmid = 14744430 | doi = 10.1016/S0092-8674(03)01074-2 | s2cid = 16783936 | doi-access = free }} 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.{{cite journal | vauthors = Frescas D, Pagano M | title = Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer | journal = Nature Reviews. Cancer | volume = 8 | issue = 6 | pages = 438–49 | date = June 2008 | pmid = 18500245 | pmc = 2711846 | doi = 10.1038/nrc2396 }} 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.{{cite journal | last1=Yu | first1=Z.-K. | last2=Gervais | first2=J. L. M. | last3=Zhang | first3=H. | title=Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins | journal=Proceedings of the National Academy of Sciences | volume=95 | issue=19 | year=1998 | pages=11324–11329 | doi=10.1073/pnas.95.19.11324 | pmid=9736735 | pmc=21641 | bibcode=1998PNAS...9511324Y | doi-access=free }}{{cite journal | last1=Bornstein | first1=G. | last2=Bloom | first2=J. | last3=Sitry-Shevah | first3=D. | last4=Nakayama | first4=K. | last5=Pagano | first5=M. | last6=Hershko | first6=A. | title=Role of the SCFSkp2 Ubiquitin Ligase in the Degradation of p21Cip1 in S Phase | journal=Journal of Biological Chemistry | volume=278 | issue=28 | year=2003 | pages=25752–25757 | doi=10.1074/jbc.m301774200 | pmid=12730199| doi-access=free }}{{cite journal | last=Kossatz | first=U. | title=Skp2-dependent degradation of p27kip1 is essential for cell cycle progression | journal=Genes & Development | volume=18 | issue=21 | year=2004 | pages=2602–2607 | doi=10.1101/gad.321004 | pmid=15520280 | pmc=525540 }} Here, SKP2 has been implicated in double negative feedback loops with both p21 and p27, that control cell cycle entry and G1/S transition.{{cite journal | last1=Barr | first1=Alexis R. | last2=Heldt | first2=Frank S. | last3=Zhang | first3=Tongli | last4=Bakal | first4=Chris | last5=Novakl | first5=Bela | title=A Dynamical Framework for the All-or-None G1/S Transition | journal=Cell Systems | volume=2 | issue=1 | year=2016 | pages=27–37 | doi=10.1016/j.cels.2016.01.001 | pmid=27136687 | pmc=4802413 }}{{cite journal | last1=Barr | first1=Alexis R. | last2=Cooper | first2=Samuel | last3=Heldt | first3=Frank S. | last4=Butera | first4=Francesca | last5=Stoy | first5=Henriette | last6=Mansfeld | first6=Jorg | last7=Novak | first7=Bela | last8=Bakal | first8=Chris |title=DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression | journal=Nature Communications | volume=8 | year=2017 | page=14728 | doi=10.1038/ncomms14728 | pmid=28317845 | pmc=5364389 | bibcode=2017NatCo...814728B }}

Skp2 behaves as an oncogene in cell systems{{cite journal | vauthors = Carrano AC, Pagano M | title = Role of the F-box protein Skp2 in adhesion-dependent cell cycle progression | journal = The Journal of Cell Biology | volume = 153 | issue = 7 | pages = 1381–90 | date = June 2001 | pmid = 11425869 | pmc = 2150734 | doi = 10.1083/jcb.153.7.1381 }} and is an established protooncogene causally involved in the pathogenesis of lymphomas.{{cite journal | vauthors = Latres E, Chiarle R, Schulman BA, Pavletich NP, Pellicer A, Inghirami G, Pagano M | title = Role of the F-box protein Skp2 in lymphomagenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 5 | pages = 2515–20 | date = February 2001 | pmid = 11226270 | pmc = 30169 | doi = 10.1073/pnas.041475098 | bibcode = 2001PNAS...98.2515L | doi-access = free }} 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).{{cite journal | vauthors = Viglietto G, Motti ML, Bruni P, Melillo RM, D'Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A, Fusco A, Santoro M | title = Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer | journal = Nature Medicine | volume = 8 | issue = 10 | pages = 1136–44 | date = October 2002 | pmid = 12244303 | doi = 10.1038/nm762 | s2cid = 6580033 }} Levels of p27^Kip1 (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 p27^Kip1 and tagging it for destruction in the proteasome system. It has been shown that as cells enter G₀ phase, reducing levels of Skp2 explain the increase in p27^Kip1, creating an apparent inverse relationship between Skp2 and p27^Kip1.

Robust evidence has been amassed that strongly suggests Skp2 plays an important role in cancer and is also involved in cancer-associated drug resistance.{{cite journal | vauthors = Wu T, Gu X, Cui H | title = Emerging Roles of SKP2 in Cancer Drug Resistance | journal = Cells | volume = 10 | issue = 5 | date = May 2021 | page = 1147 | pmid = 34068643 | pmc = 8150781 | doi = 10.3390/cells10051147 | doi-access = free }}

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. Skp2 overexpression has been seen in: lymphomas,{{cite journal | vauthors = Seki R, Okamura T, Koga H, Yakushiji K, Hashiguchi M, Yoshimoto K, Ogata H, Imamura R, Nakashima Y, Kage M, Ueno T, Sata M | title = Prognostic significance of the F-box protein Skp2 expression in diffuse large B-cell lymphoma | journal = American Journal of Hematology | volume = 73 | issue = 4 | pages = 230–5 | date = August 2003 | pmid = 12879424 | doi = 10.1002/ajh.10379 | s2cid = 1320488 | doi-access = free }} prostate cancer,{{cite journal | vauthors = Wang Z, Gao D, Fukushima H, Inuzuka H, Liu P, Wan L, Sarkar FH, Wei W | title = Skp2: a novel potential therapeutic target for prostate cancer | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1825 | issue = 1 | pages = 11–7 | date = January 2012 | pmid = 21963805 | pmc = 3242930 | doi = 10.1016/j.bbcan.2011.09.002 }} melanoma,{{cite journal | vauthors = Rose AE, Wang G, Hanniford D, Monni S, Tu T, Shapiro RL, Berman RS, Pavlick AC, Pagano M, Darvishian F, Mazumdar M, Hernando E, Osman I | title = Clinical relevance of SKP2 alterations in metastatic melanoma | journal = Pigment Cell & Melanoma Research | volume = 24 | issue = 1 | pages = 197–206 | date = February 2011 | pmid = 20883453 | pmc = 3341662 | doi = 10.1111/j.1755-148X.2010.00784.x }} nasopharyngeal carcinoma,{{cite journal | vauthors = Fang FM, Chien CY, Li CF, Shiu WY, Chen CH, Huang HY | title = Effect of S-phase kinase-associated protein 2 expression on distant metastasis and survival in nasopharyngeal carcinoma patients | journal = International Journal of Radiation Oncology, Biology, Physics | volume = 73 | issue = 1 | pages = 202–7 | date = January 2009 | pmid = 18538504 | doi = 10.1016/j.ijrobp.2008.04.008 }}{{cite journal | vauthors = Xu HM, Liang Y, Chen Q, Wu QN, Guo YM, Shen GP, Zhang RH, He ZW, Zeng YX, Xie FY, Kang TB | title = Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China | journal = Chinese Journal of Cancer | volume = 30 | issue = 3 | pages = 204–12 | date = March 2011 | pmid = 21352698 | doi = 10.5732/cjc.010.10403 | pmc=4013317}} pancreatic cancer,{{cite journal | vauthors = Schüler S, Diersch S, Hamacher R, Schmid RM, Saur D, Schneider G | title = SKP2 confers resistance of pancreatic cancer cells towards TRAIL-induced apoptosis | journal = International Journal of Oncology | volume = 38 | issue = 1 | pages = 219–25 | date = January 2011 | pmid = 21109943 | doi = 10.3892/ijo_00000841 | doi-access = free }} and breast carcinomas.{{cite journal | vauthors = Radke S, Pirkmaier A, Germain D | title = Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer | journal = Oncogene | volume = 24 | issue = 21 | pages = 3448–58 | date = May 2005 | pmid = 15782142 | doi = 10.1038/sj.onc.1208328 | doi-access = free }}{{cite journal | vauthors = Zheng WQ, Zheng JM, Ma R, Meng FF, Ni CR | title = Relationship between levels of Skp2 and P27 in breast carcinomas and possible role of Skp2 as targeted therapy | journal = Steroids | volume = 70 | issue = 11 | pages = 770–4 | date = October 2005 | pmid = 16024059 | doi = 10.1016/j.steroids.2005.04.012 | s2cid = 42043367 }} Additionally, overexpression of Skp2 is correlated with a poor prognosis in breast cancer.{{cite journal | vauthors = Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda TA, Mori M | title = Significance of skp2 expression in primary breast cancer | journal = Clinical Cancer Research | volume = 12 | issue = 4 | pages = 1215–20 | date = February 2006 | pmid = 16489076 | doi = 10.1158/1078-0432.CCR-05-1709 | s2cid = 10150993 | doi-access = }}{{cite journal |last1=Cai |first1=Zhen |last2=Moten |first2=Asad |last3=Peng |first3=Danni |last4=Hsu |first4=Che-Chia |last5=Pan |first5=Bo-Syong |last6=Manne |first6=Rajeshkumar |last7=Li |first7=Hong-yu |last8=Lin |first8=Hui-Kuan |title=The Skp2 Pathway: A Critical Target for Cancer Therapy |journal=Seminars in Cancer Biology |date=December 2020 |volume=67 |pages=16–33 |doi=10.1016/j.semcancer.2020.01.013|pmc=9201937 }} As one would expect, Skp2 overexpression promotes growth and tumorigenesis in a xenograft tumor model.{{cite journal | vauthors = Lin HK, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan CH, Yang WL, Erdjument-Bromage H, Nakayama KI, Nimer S, Tempst P, Pandolfi PP | title = Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB | journal = Nature Cell Biology | volume = 11 | issue = 4 | pages = 420–32 | date = April 2009 | pmid = 19270694 | pmc = 2830812 | doi = 10.1038/ncb1849 }} 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. This response is triggered in a p19Arf/p53-independent, but p27-dependent manner.

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.{{cite journal | vauthors = Zhang Y, Yang HY, Zhang XC, Yang H, Tsai M, Lee MH | title = Tumor suppressor ARF inhibits HER-2/neu-mediated oncogenic growth | journal = Oncogene | volume = 23 | issue = 42 | pages = 7132–43 | date = September 2004 | pmid = 15273726 | doi = 10.1038/sj.onc.1207918 | doi-access = free }}

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.{{cite journal |author15-link=Mien-Chie Hung | vauthors = Chan CH, Li CF, Yang WL, Gao Y, Lee SW, Feng Z, Huang HY, Tsai KK, Flores LG, Shao Y, Hazle JD, Yu D, Wei W, Sarbassov D, Hung MC, Nakayama KI, Lin HK | title = The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis | journal = Cell | volume = 149 | issue = 5 | pages = 1098–111 | date = May 2012 | pmid = 22632973 | pmc = 3586339 | doi = 10.1016/j.cell.2012.02.065 }}

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.{{cite journal | vauthors = Wu L, Grigoryan AV, Li Y, Hao B, Pagano M, Cardozo TJ | title = Specific small molecule inhibitors of Skp2-mediated p27 degradation | journal = Chemistry & Biology | volume = 19 | issue = 12 | pages = 1515–24 | date = December 2012 | pmid = 23261596 | pmc = 3530153 | doi = 10.1016/j.chembiol.2012.09.015 }} 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.{{cite journal | vauthors = Chan CH, Morrow JK, Li CF, Gao Y, Jin G, Moten A, Stagg LJ, Ladbury JE, Cai Z, Xu D, Logothetis CJ, Hung MC, Zhang S, Lin HK | title = Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression | journal = Cell | volume = 154 | issue = 3 | pages = 556–68 | date = August 2013 | pmid = 23911321 | pmc = 3845452 | doi = 10.1016/j.cell.2013.06.048 }} Skp2 is a potential target for pten-deficient cancers.{{cite journal | vauthors = Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, Chan CH, Yang WL, Wang J, Egia A, Nakayama KI, Cordon-Cardo C, Teruya-Feldstein J, Pandolfi PP | title = Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence | journal = Nature | volume = 464 | issue = 7287 | pages = 374–9 | date = March 2010 | pmid = 20237562 | pmc = 2928066 | doi = 10.1038/nature08815 | bibcode = 2010Natur.464..374L }}

• {{lay source |template = cite press release|url = https://www.sciencedaily.com/releases/2010/03/100317144636.htm|title = Disabling Skp2 gene helps shut down cancer growth|date= March 17, 2010 |website = ScienceDaily }}

SKP2 has been shown to interact with:

• CCNA2,{{cite journal | vauthors = Rosner M, Hengstschläger M | title = Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2 | journal = The Journal of Biological Chemistry | volume = 279 | issue = 47 | pages = 48707–15 | date = November 2004 | pmid = 15355997 | doi = 10.1074/jbc.M405528200 | doi-access = free }}{{cite journal | vauthors = Marti A, Wirbelauer C, Scheffner M, Krek W | title = Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation | journal = Nature Cell Biology | volume = 1 | issue = 1 | pages = 14–9 | date = May 1999 | pmid = 10559858 | doi = 10.1038/8984 | s2cid = 8884226 }}
• CDK2,{{cite journal | vauthors = Yam CH, Ng RW, Siu WY, Lau AW, Poon RY | title = Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2 | journal = Molecular and Cellular Biology | volume = 19 | issue = 1 | pages = 635–45 | date = January 1999 | pmid = 9858587 | pmc = 83921 | doi = 10.1128/mcb.19.1.635}}
• CDKN1A{{cite journal | vauthors = Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A | title = Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase | journal = The Journal of Biological Chemistry | volume = 278 | issue = 28 | pages = 25752–7 | date = July 2003 | pmid = 12730199 | doi = 10.1074/jbc.M301774200 | doi-access = free }}
• CDKN1B{{cite journal | vauthors = Fujita N, Sato S, Katayama K, Tsuruo T | title = Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization | journal = The Journal of Biological Chemistry | volume = 277 | issue = 32 | pages = 28706–13 | date = August 2002 | pmid = 12042314 | doi = 10.1074/jbc.M203668200 | doi-access = free }}
• CKS1B,{{cite journal | vauthors = Wang W, Ungermannova D, Chen L, Liu X | title = A negatively charged amino acid in Skp2 is required for Skp2-Cks1 interaction and ubiquitination of p27Kip1 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 34 | pages = 32390–6 | date = August 2003 | pmid = 12813041 | doi = 10.1074/jbc.M305241200 | doi-access = free }}{{cite journal | vauthors = Calvisi DF, Pinna F, Meloni F, Ladu S, Pellegrino R, Sini M, Daino L, Simile MM, De Miglio MR, Virdis P, Frau M, Tomasi ML, Seddaiu MA, Muroni MR, Feo F, Pascale RM | title = Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma | journal = Cancer Research | volume = 68 | issue = 11 | pages = 4192–200 | date = June 2008 | pmid = 18519678 | doi = 10.1158/0008-5472.CAN-07-6157 | doi-access = free }}{{cite journal | vauthors = Hao B, Zheng N, Schulman BA, Wu G, Miller JJ, Pagano M, Pavletich NP | title = Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase | journal = Molecular Cell | volume = 20 | issue = 1 | pages = 9–19 | date = October 2005 | pmid = 16209941 | doi = 10.1016/j.molcel.2005.09.003 | doi-access = free }}
• CDT1,{{cite journal | vauthors = Li X, Zhao Q, Liao R, Sun P, Wu X | title = The SCF(Skp2) ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 30854–8 | date = August 2003 | pmid = 12840033 | doi = 10.1074/jbc.C300251200 | doi-access = free}}
• CUL1{{cite journal | vauthors = Lisztwan J, Marti A, Sutterlüty H, Gstaiger M, Wirbelauer C, Krek W | title = Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway | journal = The EMBO Journal | volume = 17 | issue = 2 | pages = 368–83 | date = January 1998 | pmid = 9430629 | pmc = 1170388 | doi = 10.1093/emboj/17.2.368 }}{{cite journal | vauthors = Menon S, Tsuge T, Dohmae N, Takio K, Wei N | title = Association of SAP130/SF3b-3 with Cullin-RING ubiquitin ligase complexes and its regulation by the COP9 signalosome | journal = BMC Biochemistry | volume = 9 | pages = 1 | year = 2008 | pmid = 18173839 | pmc = 2265268 | doi = 10.1186/1471-2091-9-1 | doi-access = free }}
• E2F1,
• ORC1L,{{cite journal | vauthors = Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B | title = Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication | journal = Molecular Cell | volume = 9 | issue = 3 | pages = 481–91 | date = March 2002 | pmid = 11931757 | doi = 10.1016/S1097-2765(02)00467-7 | doi-access = free }} and
• SKP1A.{{cite journal | vauthors = Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB | title = TIP120A associates with cullins and modulates ubiquitin ligase activity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 18 | pages = 15905–10 | date = May 2003 | pmid = 12609982 | doi = 10.1074/jbc.M213070200 | doi-access = free }}{{cite journal | vauthors = Strack P, Caligiuri M, Pelletier M, Boisclair M, Theodoras A, Beer-Romero P, Glass S, Parsons T, Copeland RA, Auger KR, Benfield P, Brizuela L, Rolfe M | title = SCF(beta-TRCP) and phosphorylation dependent ubiquitinationof I kappa B alpha catalyzed by Ubc3 and Ubc4 | journal = Oncogene | volume = 19 | issue = 31 | pages = 3529–36 | date = July 2000 | pmid = 10918611 | doi = 10.1038/sj.onc.1203647 | s2cid = 24267499 | doi-access = }}{{cite journal | vauthors = Ng RW, Arooz T, Yam CH, Chan IW, Lau AW, Poon RY | title = Characterization of the cullin and F-box protein partner Skp1 | journal = FEBS Letters | volume = 438 | issue = 3 | pages = 183–9 | date = November 1998 | pmid = 9827542 | doi = 10.1016/S0014-5793(98)01299-X | s2cid = 40950881 | doi-access = free }}{{cite journal | vauthors = Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER, Finnin MS, Elledge SJ, Harper JW, Pagano M, Pavletich NP | title = Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex | journal = Nature | volume = 408 | issue = 6810 | pages = 381–6 | date = November 2000 | pmid = 11099048 | doi = 10.1038/35042620 | bibcode = 2000Natur.408..381S | s2cid = 4300503 }}{{cite journal | vauthors = Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M | title = Identification of a family of human F-box proteins | journal = Current Biology | volume = 9 | issue = 20 | pages = 1177–9 | date = October 1999 | pmid = 10531035 | doi = 10.1016/S0960-9822(00)80020-2 | s2cid = 7467493 | doi-access = free }}

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