Switch #: SWTI000693

Switch type: Avidity-sensing

Description:
Phosphorylation of two 14-3-3-binding motifs in Cyclin-dependent kinase inhibitor 1B (CDKN1B) by RAC-alpha serine/threonine-protein kinase (AKT1) and ribosomal protein S6 kinases (Ribosomal protein S6 kinase alpha-1 (RPS6KA1), Ribosomal protein S6 kinase alpha-3 (RPS6KA3)) induces binding of 14-3-3 dimer. Binding of 14-3-3 results in cytoplasmic localisation of Cyclin-dependent kinase inhibitor 1B (CDKN1B) (see switch details), thereby alleviating Cyclin-dependent kinase inhibitor 1B (CDKN1B)-mediated inhibition of cyclin-dependent kinases and cell cycle progression.

Participants:
(1) 14-3-3 protein gamma (YWHAG)
(2) 14-3-3 protein theta (YWHAQ)
(3) Cyclin-dependent kinase inhibitor 1B (CDKN1B)

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 YWHAG - YWHAQ

Interfaces
(1) 14-3-3 protein in 14-3-3 protein gamma (YWHAG)
(2) 14-3-3 protein _(3-236) in 14-3-3 protein theta (YWHAQ)

2Interaction #2 CDKN1B - Interaction #1 YWHAG - YWHAQ

Interfaces
(3) LIG_14-3-3_3 motif () in Cyclin-dependent kinase inhibitor 1B (CDKN1B)
(4) Interaction #1 YWHAG - YWHAQ

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₁₅₇ on Cyclin-dependent kinase inhibitor 1B (CDKN1B)) of the Cyclin-dependent kinase inhibitor 1B (CDKN1B) LIG_14-3-3_3 motif - 14-3-3 protein interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₁₅₇: RAC-alpha serine/threonine-protein kinase (AKT1)

2Interaction #3 CDKN1B - Interaction #1 YWHAG - YWHAQ

Interfaces
(5) LIG_14-3-3_3 motif () in Cyclin-dependent kinase inhibitor 1B (CDKN1B)
(6) Interaction #1 YWHAG - YWHAQ

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₁₉₈ on Cyclin-dependent kinase inhibitor 1B (CDKN1B)) of the Cyclin-dependent kinase inhibitor 1B (CDKN1B) LIG_14-3-3_3 motif - 14-3-3 protein interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₁₉₈: RAC-alpha serine/threonine-protein kinase (AKT1),Ribosomal protein S6 kinase alpha-1 (RPS6KA1),Ribosomal protein S6 kinase alpha-3 (RPS6KA3)

(1) Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization.
Fujita et al. J. Biol. Chem. (2002)

(2) Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer.
Viglietto et al. Nat. Med. (2002)

(3) Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization.
Fujita et al. J. Biol. Chem. (2003)

(4) 14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27(Kip1).
Sekimoto et al. EMBO J. (2004)

(5) Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer.
Motti et al. Cell Cycle (2004)