Switch #: SWTI000286

Switch type: Specificity

Switch subtype: Altered binding specificity

Description:
Transcription factor AP-1 (JUN) is primed by an unknown kinase for phosphorylation by Glycogen synthase kinase-3 beta (GSK3B), which targets JUN to the SCF ubiquitin ligase complex, F-box/WD repeat-containing protein 7 (FBXW7) that marks JUN for degradation. In v-Jun (Viral jun-transforming protein (JUN)) the residue corresponding to S243 is mutated to phenylalanine, which protects v-Jun (JUN) from degradation.

Participants:
(1) Transcription factor AP-1 (JUN)
(2) Glycogen synthase kinase-3 beta (GSK3B)
(3) F-box/WD repeat-containing protein 7 (FBXW7)

This is a sequential switch. The interactions in this switch take place in a defined order. The order is defined by numbers to the left of each interaction. More than one interaction can occur in each step, these interactions occur independently but are necessary for future step

1Interaction #1 JUN - GSK3B

Is mutually exclusive with Interaction #2 JUN - FBXW7

Interfaces
(1) MOD_GSK3_1 motif (₂₃₆PGETPPLS₂₄₃) in Transcription factor AP-1 (JUN)
(2) Protein kinase domain _(56-340) in Glycogen synthase kinase-3 beta (GSK3B)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₂₄₃ on Transcription factor AP-1 (JUN)) of the Transcription factor AP-1 (JUN) MOD_GSK3_1 motif - Glycogen synthase kinase-3 beta (GSK3B) Protein kinase domain interaction

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: S₂₄₃ : CK2_group, Glycogen synthase kinase-3 alpha (GSK3A), Casein kinase II subunit alpha (CSNK2A1), Glycogen synthase kinase-3 beta (GSK3B).

2Interaction #2 JUN - FBXW7

Requires Interaction #1 JUN - GSK3B
Is mutually exclusive with Interaction #1 JUN - GSK3B

Interfaces
(3) DEG_SCF_FBW7_1 motif (₂₃₆PGETPPLS₂₄₃) in Transcription factor AP-1 (JUN)
(4) WD domain, G-beta repeat _(371-407) and _(411-447) and _(451-487) and _(491-527) and _(531-567) and _(571-607) and _(611-650) in F-box/WD repeat-containing protein 7 (FBXW7)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₂₃₉ and S₂₄₃ on Transcription factor AP-1 (JUN)) of the Transcription factor AP-1 (JUN) DEG_SCF_FBW7_1 motif - F-box/WD repeat-containing protein 7 (FBXW7) WD domain, G-beta repeat interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₂₃₉: Glycogen synthase kinase-3 beta (GSK3B)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₂₃₉ : GSK-3_group, Glycogen synthase kinase-3 beta (GSK3B), Glycogen synthase kinase-3 alpha (GSK3A). S₂₄₃ : CK2_group, Glycogen synthase kinase-3 alpha (GSK3A), Casein kinase II subunit alpha (CSNK2A1), Glycogen synthase kinase-3 beta (GSK3B).

(1) The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase.
Wei et al. Cancer Cell (2005)