Switch #: SWTI000279

Switch type: Specificity

Switch subtype: Altered binding specificity

Description:
CDK8/9 phosphorylates Mothers against decapentaplegic homolog 3 (SMAD3) at T179 and S208. Phosphorylation of T179 creates a binding site for the WW domain of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), while phosphorylation of S208 primes SMAD3 for phosphorylation of S204 by Glycogen synthase kinase-3 beta (GSK3B). The pS204-pS208 forms a binding site for the third WW domain of E3 ubiquitin-protein ligase NEDD4-like (NEDD4L), whose second WW domain will displace the WW domain of PIN1 at the pT179-PY box site of SMAD3. This regulation couples SMAD3 activation to SMAD3 destruction in an ordered fashion. See also switch details and switch details.

Participants:
(1) Mothers against decapentaplegic homolog 3 (SMAD3)
(2) Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)
(3) Glycogen synthase kinase-3 beta (GSK3B)
(4) E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

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 SMAD3 - PIN1

Is mutually exclusive with Interaction #4 SMAD3 - NEDD4L

Interfaces
(1) DOC_WW_Pin1_4 motif (₁₇₆IPETPP₁₈₁) in Mothers against decapentaplegic homolog 3 (SMAD3)
(2) WW domain _(7-37) in Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₁₇₉ on Mothers against decapentaplegic homolog 3 (SMAD3)) of the Mothers against decapentaplegic homolog 3 (SMAD3) DOC_WW_Pin1_4 motif - Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) WW domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₁₇₉: CDC2/CDKX subfamily

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₁₇₉ : Cyclin-dependent kinase 2 (CDK2), Cyclin-dependent kinase 2 (Cdk2), Cyclin-dependent kinase 4 (Cdk4), Cyclin-dependent kinase 8 (CDK8), Cyclin-dependent kinase 9 (CDK9), Cyclin-dependent kinase 4 (CDK4), Mitogen-activated protein kinase 1 (MAPK1).

Additional Information
Affinity : T179: >100 µM, pT179: 12.6 µM
Structural information: 2LB3

1Interaction #2 SMAD3 - GSK3B

Interfaces
(3) MOD_GSK3_1 motif (₂₀₁DAGSPNLS₂₀₈) in Mothers against decapentaplegic homolog 3 (SMAD3)
(4) Protein kinase domain _(56-340) in Glycogen synthase kinase-3 beta (GSK3B)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₂₀₈ on Mothers against decapentaplegic homolog 3 (SMAD3)) of the Mothers against decapentaplegic homolog 3 (SMAD3) MOD_GSK3_1 motif - Glycogen synthase kinase-3 beta (GSK3B) Protein kinase domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₂₀₈: CDC2/CDKX subfamily

2Interaction #3 SMAD3 - NEDD4L

Requires Interaction #2 SMAD3 - GSK3B

Interfaces
(5) ELM:LIG_WW_Nedd4L motif (₂₀₃GSPNLSPN₂₁₀) in Mothers against decapentaplegic homolog 3 (SMAD3)
(6) WW domain _(499-528) in E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₂₀₄ and S₂₀₈ on Mothers against decapentaplegic homolog 3 (SMAD3)) of the Mothers against decapentaplegic homolog 3 (SMAD3) LIG_WW_Nedd4L motif - E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) WW domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₂₀₄: Glycogen synthase kinase-3 beta (GSK3B); S₂₀₈: CDC2/CDKX subfamily

Additional Information
Affinity : T179: 60 µM, pT179: 8.5 µM, pT179-S204-pS208: 2.9 µM, pT179-pS204-pS208: 0.7 µM
Structural information: 2LAJ

3Interaction #4 SMAD3 - NEDD4L

Requires Interaction #3 SMAD3 - NEDD4L
Is mutually exclusive with Interaction #1 SMAD3 - PIN1

Interfaces
(7) LIG_WW_1 motif (₁₈₁PPGY₁₈₄) in Mothers against decapentaplegic homolog 3 (SMAD3)
(8) WW domain _(387-416) in E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

Interaction Regulation
PTM-dependent Enhancement (Phosphorylation of T₁₇₉ on Mothers against decapentaplegic homolog 3 (SMAD3)) of the Mothers against decapentaplegic homolog 3 (SMAD3) LIG_WW_1 motif - E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) WW domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₁₇₉: CDC2/CDKX subfamily

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₁₇₉ : Cyclin-dependent kinase 2 (CDK2), Cyclin-dependent kinase 2 (Cdk2), Cyclin-dependent kinase 4 (Cdk4), Cyclin-dependent kinase 8 (CDK8), Cyclin-dependent kinase 9 (CDK9), Cyclin-dependent kinase 4 (CDK4), Mitogen-activated protein kinase 1 (MAPK1).

Additional Information
Affinity : T179: 60 µM, pT179: 8.5 µM, pT179-S204-pS208: 2.9 µM, pT179-pS204-pS208: 0.7 µM
Structural information: 2LB2

(1) A Smad action turnover switch operated by WW domain readers of a phosphoserine code.
Aragón et al. Genes Dev. (2011)