Thr187
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Home > Phosphorylation Site Page: > Thr187  -  p27Kip1 (human)

Site Information
NAGsVEQtPKKPGLR   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447875

In vivo Characterization
Methods used to characterize site in vivo:
[32P] ATP in vitro ( 12 ) , [32P] bio-synthetic labeling ( 36 , 39 ) , electrophoretic mobility shift ( 39 ) , immunoprecipitation ( 16 , 17 , 18 , 19 ) , mass spectrometry ( 8 ) , mutation of modification site ( 4 , 11 , 12 , 14 , 16 , 24 , 25 , 26 , 27 , 29 , 31 , 32 , 36 , 39 , 41 ) , phospho-antibody ( 5 , 7 , 10 , 11 , 15 , 17 , 18 , 19 , 20 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 36 , 37 , 38 ) , phosphoamino acid analysis ( 24 , 39 ) , phosphopeptide mapping ( 39 ) , western blotting ( 4 , 5 , 7 , 10 , 11 , 15 , 16 , 17 , 18 , 19 , 20 , 22 , 23 , 25 , 26 , 27 , 31 , 38 , 41 )
Disease tissue studied:
bone cancer ( 27 ) , brain cancer ( 14 , 38 ) , glioblastoma ( 14 , 38 ) , glioma ( 14 , 38 ) , breast cancer ( 3 , 8 , 17 , 19 , 25 , 31 ) , breast ductal carcinoma ( 8 ) , colorectal cancer ( 20 ) , colorectal carcinoma ( 20 ) , leukemia ( 27 ) , chronic myelogenous leukemia ( 27 ) , neuroblastoma ( 18 ) , ovarian cancer ( 5 , 14 ) , multiple myeloma ( 24 ) , prostate cancer ( 11 ) , cancer, squamous cell carcinoma ( 14 )
Relevant cell line - cell type - tissue:
'muscle, smooth'-'heart, artery' ( 7 ) , 293 (epithelial) ( 16 , 25 , 29 ) , 3T3 (fibroblast) [SHP-2 (mouse), homozygous knockout] ( 39 ) , AGS-B (gastric) ( 30 ) , BC-1 (B lymphocyte) ( 27 ) , breast ( 8 ) , BT-474 (breast cell) ( 31 ) , corneal ( 22 ) , COS (fibroblast) ( 39 ) , CWR22Rv1 (prostate cell) ( 11 ) , E.coli (bacterial) ( 12 ) , fibroblast ( 25 ) , HDE-14 (lymphoblastoid) ( 28 ) , HEK293T (epithelial) ( 24 , 39 ) , HeLa (cervical) ( 15 , 24 , 26 , 39 , 41 ) , HEY (ovarian) ( 5 ) , HMEC (endothelial) ( 19 ) , HT-29 (intestinal) ( 20 ) , HTR8/SVneo (trophoblast) ( 10 ) , IMR-90 (fibroblast) ( 37 ) , K562 (erythroid) ( 24 ) , LAN-1 (neural crest) ( 18 ) , LoVo (intestinal) ( 20 ) , MCF-7 (breast cell) ( 19 , 23 , 24 , 25 , 32 ) , MDA-MB-231 (breast cell) ( 3 , 17 ) , MDA-MB-468 (breast cell) ( 17 , 29 ) , MDAH2774 (ovarian) ( 14 ) , MEF (fibroblast) ( 25 ) , MEF (fibroblast) [p27Kip1 (human)] ( 24 ) , MEF (fibroblast) [PIN1 (human), transfection] ( 16 ) , Rat1 (fibroblast) ( 36 ) , RPMI-8266 (plasma cell) ( 24 ) , SCC-9 (squamous) ( 14 ) , SKBr3 (breast cell) ( 31 ) , U2OS (bone cell) ( 27 ) , U87MG (glial) ( 14 , 38 )

Upstream Regulation
Regulatory protein:
CAMK2N1 (human) ( 20 ) , CCNE1 (human) ( 38 ) , CDK5 (human) ( 5 ) , EGLN3 (human) ( 6 ) , MARCKS (human) ( 7 ) , MIF4GD (human) ( 4 ) , PFKFB3 (human) ( 15 ) , SKP2 (human) ( 26 ) , TRIM21 (human) ( 26 ) , WISP2 (human) ( 3 )
Kinases, in vitro:
Abl (human) ( 12 ) , CDK1 (human) ( 9 ) , CDK2 (human) ( 2 , 9 , 21 , 24 , 34 , 36 , 42 ) , CDK2 (mouse) ( 40 ) , CDK6 (human) ( 27 ) , ERK1 (human) ( 40 ) , ERK2 (human) ( 39 , 40 )
Treatments:
A-443654 ( 18 ) , anti-HER2 ( 31 ) , eflornithine ( 18 ) , F2,6BP ( 15 ) , FGF2 ( 22 ) , GGTI-2417 ( 17 ) , hypoxia ( 6 ) , LY294002 ( 3 , 18 , 19 , 22 , 29 ) , MG132 ( 30 ) , Nodal ( 10 ) , phorbol_ester ( 27 ) , retinoic_acid ( 28 ) , serum ( 19 ) , siRNA ( 20 , 26 ) , spermidine ( 18 ) , U0126 ( 20 )

Downstream Regulation
Effects of modification on p27Kip1:
molecular association, regulation ( 16 , 19 , 21 , 24 , 33 , 36 , 42 ) , protein conformation ( 2 , 16 ) , protein degradation ( 4 , 17 , 24 , 25 , 26 , 40 , 41 , 42 ) , protein stabilization ( 16 ) , ubiquitination ( 41 )
Effects of modification on biological processes:
cell cycle regulation ( 2 , 24 , 25 , 31 , 42 )
Induce interaction with:
CCND1 (human) ( 19 ) , CDK4 (human) ( 19 ) , CKS1 (human) ( 16 , 21 , 33 ) , CUL1 (human) ( 42 ) , PIN1 (human) ( 16 ) , SKP1A (human) ( 42 ) , SKP2 (human) ( 21 , 33 , 36 , 42 )
Inhibit interaction with:
CDK2 (human) ( 24 )

References 

1

Tsytlonok M, et al. (2019) Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation. Nat Commun 10, 1676
30976006   Curated Info

2

Das RK, et al. (2016) Cryptic sequence features within the disordered protein p27Kip1 regulate cell cycle signaling. Proc Natl Acad Sci U S A 113, 5616-21
27140628   Curated Info

3

Haque I, et al. (2015) CCN5/WISP-2 promotes growth arrest of triple-negative breast cancer cells through accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation. Oncogene 34, 3152-63
25132260   Curated Info

4

Wan C, et al. (2015) MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability. Oncogene 34, 237-45
24336329   Curated Info

5

Zhang S, et al. (2015) CDK5 Regulates Paclitaxel Sensitivity in Ovarian Cancer Cells by Modulating AKT Activation, p21Cip1- and p27Kip1-Mediated G1 Cell Cycle Arrest and Apoptosis. PLoS One 10, e0131833
26146988   Curated Info

6

Högel H, Miikkulainen P, Bino L, Jaakkola PM (2015) Hypoxia inducible prolyl hydroxylase PHD3 maintains carcinoma cell growth by decreasing the stability of p27. Mol Cancer 14, 143
26223520   Curated Info

7

Yu D, et al. (2015) MARCKS Signaling Differentially Regulates Vascular Smooth Muscle and Endothelial Cell Proliferation through a KIS-, p27kip1- Dependent Mechanism. PLoS One 10, e0141397
26528715   Curated Info

8

Mertins P, et al. (2014) Ischemia in tumors induces early and sustained phosphorylation changes in stress kinase pathways but does not affect global protein levels. Mol Cell Proteomics 13, 1690-704
24719451   Curated Info

9

Rossi M, et al. (2013) Regulation of the CRL4(Cdt2) Ubiquitin Ligase and Cell-Cycle Exit by the SCF(Fbxo11) Ubiquitin Ligase. Mol Cell 49, 1159-66
23478441   Curated Info

10

Nadeem L, et al. (2013) Cytoplasmic mislocalization of p27 and CDK2 mediates the anti-migratory and anti-proliferative effects of Nodal in human trophoblast cells. J Cell Sci 126, 445-53
23230143   Curated Info

11

Fang Z, et al. (2012) Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective TORC2 Activation. J Biol Chem 287, 2090-8
22139837   Curated Info

12

Ou L, et al. (2011) Incomplete folding upon binding mediates Cdk4/cyclin D complex activation by tyrosine phosphorylation of inhibitor p27 protein. J Biol Chem 286, 30142-51
21715330   Curated Info

13

Pierantoni GM, et al. (2011) Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility. J Biol Chem 286, 29005-13
21715331   Curated Info

14

Schiappacassi M, et al. (2011) Role of T198 modification in the regulation of p27(Kip1) protein stability and function. PLoS One 6, e17673
21423803   Curated Info

15

Yalcin A, et al. (2009) Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases. J Biol Chem 284, 24223-32
19473963   Curated Info

16

Zhou W, et al. (2009) Pin1 catalyzes conformational changes of Thr-187 in p27Kip1 and mediates its stability through a polyubiquitination process. J Biol Chem 284, 23980-8
19584057   Curated Info

17

Kazi A, et al. (2009) Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol Cell Biol 29, 2254-63
19204084   Curated Info

18

Koomoa DL, et al. (2008) Ornithine decarboxylase inhibition by alpha-difluoromethylornithine activates opposing signaling pathways via phosphorylation of both Akt/protein kinase B and p27Kip1 in neuroblastoma. Cancer Res 68, 9825-31
19047162   Curated Info

19

Larrea MD, et al. (2008) Phosphorylation of p27Kip1 regulates assembly and activation of cyclin D1-Cdk4. Mol Cell Biol 28, 6462-72
18710949   Curated Info

20

Wang C, et al. (2008) A novel endogenous human CaMKII inhibitory protein suppresses tumor growth by inducing cell cycle arrest via p27 stabilization. J Biol Chem 283, 11565-74
18305109   Curated Info

21

Xu S, et al. (2007) Substrate recognition and ubiquitination of SCFSkp2/Cks1 ubiquitin-protein isopeptide ligase. J Biol Chem 282, 15462-70
17409098   Curated Info

22

Lee JG, Kay EP (2007) Two populations of p27 use differential kinetics to phosphorylate Ser-10 and Thr-187 via phosphatidylinositol 3-Kinase in response to fibroblast growth factor-2 stimulation. J Biol Chem 282, 6444-54
17209046   Curated Info

23

Chu I, et al. (2007) p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2. Cell 128, 281-94
17254967   Curated Info

24

Grimmler M, et al. (2007) Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell 128, 269-80
17254966   Curated Info

25

Kossatz U, et al. (2006) C-terminal phosphorylation controls the stability and function of p27kip1. EMBO J 25, 5159-70
17053782   Curated Info

26

Sabile A, et al. (2006) Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol Cell Biol 26, 5994-6004
16880511   Curated Info

27

Sarek G, Järviluoma A, Ojala PM (2006) KSHV viral cyclin inactivates p27KIP1 through Ser10 and Thr187 phosphorylation in proliferating primary effusion lymphomas. Blood 107, 725-32
16160006   Curated Info

28

Zancai P, et al. (2005) Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins. Oncogene 24, 2483-94
15735731   Curated Info

29

Motti ML, et al. (2004) Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer. Cell Cycle 3, 1074-80
15280662   Curated Info

30

Eguchi H, Herschenhous N, Kuzushita N, Moss SF (2003) Helicobacter pylori increases proteasome-mediated degradation of p27(kip1) in gastric epithelial cells. Cancer Res 63, 4739-46
12907657   Curated Info

31

Le XF, et al. (2003) The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. J Biol Chem 278, 23441-50
12700233   Curated Info

32

Connor MK, et al. (2003) CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. Mol Biol Cell 14, 201-13
12529437   Curated Info

33

Sitry D, et al. (2002) Three different binding sites of Cks1 are required for p27-ubiquitin ligation. J Biol Chem 277, 42233-40
12140288   Curated Info

34

Fujita N, Sato S, Katayama K, Tsuruo T (2002) Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem 277, 28706-13
12042314   Curated Info

35

Ishida N, et al. (2002) Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J Biol Chem 277, 14355-8
11889117   Curated Info

36

Rodier G, et al. (2001) p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20, 6672-82
11726503   Curated Info

37

Carrano AC, Pagano M (2001) Role of the F-box protein Skp2 in adhesion-dependent cell cycle progression. J Cell Biol 153, 1381-90
11425869   Curated Info

38

Mamillapalli R, et al. (2001) PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2). Curr Biol 11, 263-7
11250155   Curated Info

39

Ishida N, Kitagawa M, Hatakeyama S, Nakayama K (2000) Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability. J Biol Chem 275, 25146-54
10831586   Curated Info

40

Lenferink AE, et al. (2000) Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice. Proc Natl Acad Sci U S A 97, 9609-14
10931950   Curated Info

41

Podust VN, et al. (2000) A Nedd8 conjugation pathway is essential for proteolytic targeting of p27Kip1 by ubiquitination. Proc Natl Acad Sci U S A 97, 4579-84
10781063   Curated Info

42

Tsvetkov LM, et al. (1999) p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol 9, 661-4
10375532   Curated Info