Switch #: SWTI000355

Switch type: Avidity-sensing

Description:
Phosphorylation of two 14-3-3-binding motifs in Forkhead box protein O3 (FOXO3) by RAC-alpha serine/threonine-protein kinase (AKT1) induces high-avidity binding to dimeric 14-3-3 protein beta/alpha (YWHAB). This interaction results in cytoplasmic retention and inactivation of Forkhead box protein O3 (FOXO3).

Participants:
(1) 14-3-3 protein beta/alpha (YWHAB)
(2) Forkhead box protein O3 (FOXO3)

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 YWHAB - YWHAB

Interfaces
(1) 14-3-3 protein in 14-3-3 protein beta/alpha (YWHAB)
(2) 14-3-3 protein _(5-238) in 14-3-3 protein beta/alpha (YWHAB)

2Interaction #2 FOXO3 - Interaction #1 YWHAB - YWHAB

Requires Interaction #1 YWHAB - YWHAB

Interfaces
(3) LIG_14-3-3_3 motif (₂₅₀RAVSMD₂₅₅) in Forkhead box protein O3 (FOXO3)
(4) Interaction #1 YWHAB - YWHAB

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₂₅₃ on Forkhead box protein O3 (FOXO3)) of the Forkhead box protein O3 (FOXO3) LIG_14-3-3_3 motif - 14-3-3 protein interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₂₅₃: RAC-alpha serine/threonine-protein kinase (AKT1)

2Interaction #3 FOXO3 - Interaction #1 YWHAB - YWHAB

Requires Interaction #1 YWHAB - YWHAB

Interfaces
(5) LIG_14-3-3_3 motif (₂₉RSCTWP₃₄) in Forkhead box protein O3 (FOXO3)
(6) Interaction #1 YWHAB - YWHAB

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₃₂ on Forkhead box protein O3 (FOXO3)) of the Forkhead box protein O3 (FOXO3) LIG_14-3-3_3 motif - 14-3-3 protein interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₃₂: RAC-alpha serine/threonine-protein kinase (AKT1)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₃₂ : PKB_group, SGK_group, RAC-alpha serine/threonine-protein kinase (AKT1), RAC-alpha serine/threonine-protein kinase (Akt1), Serine/threonine-protein kinase pim-1 (PIM1).

(1) A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span.
Lehtinen et al. Cell (2006)

(2) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
Brunet et al. Cell (1999)

Other switches involving participants
14-3-3 protein beta/alpha (YWHAB) - 8 more (view)

Other switches involving interfaces
14-3-3 protein - 38 more (view)
LIG_14-3-3_3 - 16 more (view)