Switch #: SWTI000285

Switch type: Specificity

Switch subtype: Altered binding specificity

Description:
Phosphorylation of Myc proto-oncogene protein (MYC) at S62 by Mitogen-activated protein kinase 1 (MAPK1) primes MYC for phosphorylation by Glycogen synthase kinase-3 beta (GSK3B), which targets MYC to the SCF ubiquitin ligase complex, F-box/WD repeat-containing protein 7 (FBXW7) that marks MYC for degradation.

Participants:
(1) Myc proto-oncogene protein (MYC)
(2) Mitogen-activated protein kinase 1 (MAPK1)
(3) Glycogen synthase kinase-3 beta (GSK3B)
(4) 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 MYC - MAPK1

Is mutually exclusive with

Interfaces
(1) MOD_ProDKin_1 motif (₅₉PPLSPSR₆₅) in Myc proto-oncogene protein (MYC)
(2) Protein kinase domain _(25-313) in Mitogen-activated protein kinase 1 (MAPK1)

2Interaction #2 MYC - GSK3B

Requires Interaction #1 MYC - MAPK1
Is mutually exclusive with

Interfaces
(3) MOD_GSK3_1 motif (₅₅LLPTPPLS₆₂) in Myc proto-oncogene protein (MYC)
(4) Protein kinase domain _(56-340) in Glycogen synthase kinase-3 beta (GSK3B)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₆₂ on Myc proto-oncogene protein (MYC)) of the Myc proto-oncogene protein (MYC) MOD_GSK3_1 motif - Glycogen synthase kinase-3 beta (GSK3B) Protein kinase domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₆₂: Mitogen-activated protein kinase 1 (MAPK1)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: S₆₂ : Cyclin-dependent kinase 5 (CDK5), Mitogen-activated protein kinase 3 (Mapk3), ERK2, Mitogen-activated protein kinase 8 (MAPK8), Mitogen-activated protein kinase 9 (MAPK9), Mitogen-activated protein kinase 10 (MAPK10), Serine/threonine-protein kinase mTOR (MTOR), Mitogen-activated protein kinase 1 (MAPK1).

3Interaction #3 MYC - FBXW7

Requires Interaction #2 MYC - GSK3B
Is mutually exclusive with

Interfaces
(5) DEG_SCF_FBW7_1 motif (₅₅LLPTPPLS₆₂) in Myc proto-oncogene protein (MYC)
(6) 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 T₅₈ and S₆₂ on Myc proto-oncogene protein (MYC)) of the Myc proto-oncogene protein (MYC) 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: T₅₈: Glycogen synthase kinase-3 beta (GSK3B); S₆₂: Mitogen-activated protein kinase 1 (MAPK1)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₅₈ : GSK-3_group, Mitogen-activated protein kinase 1 (MAPK1), Glycogen synthase kinase-3 beta (Gsk3b), Mitogen-activated protein kinase 10 (MAPK10), Glycogen synthase kinase-3 alpha (GSK3A), Glycogen synthase kinase-3 beta (GSK3B). S₆₂ : Cyclin-dependent kinase 5 (CDK5), Mitogen-activated protein kinase 3 (Mapk3), ERK2, Mitogen-activated protein kinase 8 (MAPK8), Mitogen-activated protein kinase 9 (MAPK9), Mitogen-activated protein kinase 10 (MAPK10), Serine/threonine-protein kinase mTOR (MTOR), Mitogen-activated protein kinase 1 (MAPK1).

(1) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation.
Welcker et al. Proc. Natl. Acad. Sci. U.S.A. (2004)

Other switches involving participants
Glycogen synthase kinase-3 beta (GSK3B) - 18 more (view)
Myc proto-oncogene protein (MYC) - 4 more (view)
F-box/WD repeat-containing protein 7 (FBXW7) - 8 more (view)

Other switches involving interfaces
Protein kinase domain - 35 more (view)
MOD_GSK3_1 - 18 more (view)
WD domain, G-beta repeat - 36 more (view)
DEG_SCF_FBW7_1 - 4 more (view)