Tyrosine kinases phosphorylate Cip/Kip inhibitors bound to CDK4/6:CCND complexes

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R-HSA-8942607
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Reaction [transition]
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Homo sapiens
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Phosphorylation of Cip/Kip cyclin-dependent kinase (CDK) inhibitors CDKN1A (p21Cip), CDKN1B (p27Kip1) and CDKN1C (p57Kip2) on conserved tyrosine residues Y77, Y88 and Y91, respectively, can convert them from bound inhbitors to bound non-inhibitors of CDK4 or CDK6 complexes with D cyclins by dislodging them from the active site of CDK4 or CDK6. This mechanism was studied in most detail on the example of CDKN1B associated with the CDK2:CCNA complex (Grimmler et al. 2007) and the CDK4:CCND1 complex (James et al. 2008, Patel et al. 2015). For a review of this topic, please refer to Blain 2008.
CDKN1A can be phosphorylated at tyrosine residue Y77 by protein tyrosine kinase ABL1 (Hukkelhoven et al. 2012). CDKN1B can be phosphorylated at tyrosine residue Y88, and probably also at the adjacent Y89, by protein tyrosine kinases ABL1 (Grimmler et al. 2007, James et al. 2008, Ray et al. 2009, Ou et al. 2011), LYN (Grimmler et al. 2007), SRC (Larrea et al. 2008), JAK2 (Jakel et al. 2011) and PTK6 (Patel et al. 2015). CDKN1C can be phosphorylated at tyrosine residue Y91 by protein tyrosine kinase ABL1 (Borriello et al. 2011).
Dislodgment of the tyrosine phosphorylated 3-10 helix of Cip/Kip CDK inhibitors from the active site of cyclin D-bound CDK4 or CDK6 results in increased catalytic activity of CDK4 or CDK6 by allowing ATP binding to the active site, but also by enabling activating phosphorylation of the T-loop of CDK4 or CDK6 phosphorylation by CDK7 in complex with cyclin H (Ray et al. 2009).
SRC-mediated phosphorylation of CDKN1B on tyrosine residue Y88 was shown to reduce protein stability of CDKN1B (Chu et al. 2007).
Without overexpression of BCR-ABL or SRC-family tyrosine kinases in several cell systems, tyrosine phosphorylated p27 is either undetectable or a very low abundance species (Ishida et al. 2000, Jaimes et al. 2008, Grimmler et al. 2007) that does not bind preferentially to CDK4 (Jaimes et al. 2008). Therefore, tyrosine phosphorylation of p27 is unlikely to be the sole explanation of the full activity of p27-bound CDK4:CCND complexes reported in previous studies (Blain et al. 1997, Coulonval et al. 2003, Bockstaele et al. 2006). It has been proposed that stoichiometry of the Cip/Kip complex with CDK4 or CDK6 and cyclin D, in addition to or alternative to tyrosine phosphorylation of Cip/Kip CDK inhibitors, determines their inhibitory role where binding of more than one molecule of CDKN1A, CDKN1B or CDKN1C would be needed to achieve inhibition of the CDK4/6:CCND complex (reviewed by Paternot et al. 2010).

Literature References
PubMed ID Title Journal Year
14597415 The cyclin D3-CDK4-p27kip1 holoenzyme in thyroid epithelial cells: activation by TSH, inhibition by TGFbeta, and phosphorylations of its subunits demonstrated by two-dimensional gel electrophoresis

Coulonval, K, Bockstaele, L, Paternot, S, Dumont, JE, Roger, PP

Exp. Cell Res. 2003
20952511 p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells

Borriello, A, Caldarelli, I, Bencivenga, D, Cucciolla, V, Oliva, A, Usala, E, Danise, P, Ronzoni, L, Perrotta, S, Della Ragione, F

Carcinogenesis 2011
9325318 Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4

Blain, SW, Montalvo, E, Massagué, J

J. Biol. Chem. 1997
18414028 Switching cyclin D-Cdk4 kinase activity on and off

Blain, SW

Cell Cycle 2008
21423214 Phosphorylation of p27Kip1 by JAK2 directly links cytokine receptor signaling to cell cycle control

Jäkel, H, Weinl, C, Hengst, L

Oncogene 2011
20107323 Rb inactivation in cell cycle and cancer: the puzzle of highly regulated activating phosphorylation of CDK4 versus constitutively active CDK-activating kinase

Paternot, S, Bockstaele, L, Bisteau, X, Kooken, H, Coulonval, K, Roger, PP

Cell Cycle 2010
17908796 Differential modification of p27Kip1 controls its cyclin D-cdk4 inhibitory activity

James, MK, Ray, A, Leznova, D, Blain, SW

Mol. Cell. Biol. 2008
10831586 Phosphorylation at serine 10, a major phosphorylation site of p27(Kip1), increases its protein stability

Ishida, N, Kitagawa, M, Hatakeyama, S, Nakayama, K

J. Biol. Chem. 2000
25733683 Brk/Protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4

Patel, P, Asbach, B, Shteyn, E, Gomez, C, Coltoff, A, Bhuyan, S, Tyner, AL, Wagner, R, Blain, SW

Mol. Cell. Biol. 2015
19075005 p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes

Ray, A, James, MK, Larochelle, S, Fisher, RP, Blain, SW

Mol. Cell. Biol. 2009
18710949 Phosphorylation of p27Kip1 regulates assembly and activation of cyclin D1-Cdk4

Larrea, MD, Liang, J, Da Silva, T, Hong, F, Shao, SH, Han, K, Dumont, D, Slingerland, JM

Mol. Cell. Biol. 2008
21715330 Incomplete folding upon binding mediates Cdk4/cyclin D complex activation by tyrosine phosphorylation of inhibitor p27 protein

Ou, L, Ferreira, AM, Otieno, S, Xiao, L, Bashford, D, Kriwacki, RW

J. Biol. Chem. 2011
16782892 Regulated activating Thr172 phosphorylation of cyclin-dependent kinase 4(CDK4): its relationship with cyclins and CDK "inhibitors"

Bockstaele, L, Kooken, H, Libert, F, Paternot, S, Dumont, JE, de Launoit, Y, Roger, PP, Coulonval, K

Mol Cell Biol 2006
17254966 Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases

Grimmler, M, Wang, Y, Mund, T, Cilensek, Z, Keidel, EM, Waddell, MB, Jäkel, H, Kullmann, M, Kriwacki, RW, Hengst, L

Cell 2007
17254967 p27 phosphorylation by Src regulates inhibition of cyclin E-Cdk2

Chu, I, Sun, J, Arnaout, A, Kahn, H, Hanna, W, Narod, S, Sun, P, Tan, CK, Hengst, L, Slingerland, J

Cell 2007
23007395 Tyrosine phosphorylation of the p21 cyclin-dependent kinase inhibitor facilitates the development of proneural glioma

Hukkelhoven, E, Liu, Y, Yeh, N, Ciznadija, D, Blain, SW, Koff, A

J. Biol. Chem. 2012
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protein tyrosine kinase activity of (p-Y342-PTK6,p-Y397-LYN,p-Y226,Y393-ABL1,p-Y419-SRC,p-5Y-JAK2) [cytosol]
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