Switch #:
SWTI000456
Switch type:
Binary
Switch subtype:
Physicochemical compatibility

Description:
Phosphorylation of Cellular tumor antigen p53 (TP53) on T18 (in vitro by Casein kinase I subfamily, requiring prior phosphorylation of S15) inhibits its binding to E3 ubiquitin-protein ligase Mdm2 (MDM2). In vivo, T18 is phosphorylated in response to DNA damage.

Participants:
(1) Cellular tumor antigen p53 (TP53)
(2) E3 ubiquitin-protein ligase Mdm2 (MDM2)

Interactions
Interaction #1 TP53 - MDM2

Interfaces
(1) DEG_MDM2_1 motif (19FSDLWKLL26) in Cellular tumor antigen p53 (TP53)
(2) SWIB/MDM2 domain (27-102) in E3 ubiquitin-protein ligase Mdm2 (MDM2)

Interaction Regulation
PTM-dependent Abrogation (Phosphorylation of T18 on Cellular tumor antigen p53 (TP53)) of the Cellular tumor antigen p53 (TP53) DEG_MDM2_1 motif - E3 ubiquitin-protein ligase Mdm2 (MDM2) SWIB/MDM2 domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T18: Casein kinase I subfamily

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T18 : CK1_group, Dual specificity protein kinase TTK (TTK), 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1), Casein kinase I isoform alpha (CSNK1A1), Casein kinase I isoform delta (CSNK1D), Serine/threonine-protein kinase Chk1 (CHEK1), Serine/threonine-protein kinase Chk2 (CHEK2), Death-associated protein kinase 1 (DAPK1), DNA-dependent protein kinase catalytic subunit (PRKDC), Serine/threonine-protein kinase VRK1 (VRK1).

Additional Information
Structural information: 1YCR
Context
Switch localisation
ELM curated: nucleus, cytosol
Inferred: nucleolus, cytosol

Switch cell cycle phase
Curated: DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest

Switch pathways
Inferred: PI3K-Akt signaling pathway
References

(1) Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding.
Sakaguchi et al. J. Biol. Chem. (2000)

(2) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.
Kussie et al. Science (1996)




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