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| Domain hiding | Altered binding specificity | Motif hiding | Composite binding site formation |
| Uncategorised | Rheostatic | Allostery | Avidity-sensing |
| Physicochemical compatibility | Pre-translational | Competition |
| Protein | Start | End | Switch Type | Switch Subtype | Switch Description | Information |
DOC_AGCK_PIF_1 - The DOC_AGCK_PIF_1 motif contains a phosphorylatable serine/threonine residue that allows fine-tuning of the affinity of the motif for the PIF pocket, with the phosphorylated motif showing a higher affinity. | |||||||
| AKT1_HUMAN | 469 | 474 | Binary | Physicochemical compatibility | Phosphorylation of S473 in the PIF motif of RAC-alpha serine/threonine-protein kinase (AKT1) by Serine/threonine-protein kinase mTOR (MTOR) (as part of mTORC2 complex) induces intramolecular interaction with the PIF-binding pocket, resulting in cis-activation of RAC-alpha serine/threonine-protein kinase (AKT1). Dephosphorylation of the PIF motif by PHLPP1/2 (PHLPP1 for Akt2/3 and PHLPP2 for Akt1/3) results in reduced Akt activity, probably by disrupting the interaction with the Akt PIF pocket and thus cis-activation. | ||
| KPCB_HUMAN | 656 | 661 | Binary | Physicochemical compatibility | Dephosphorylation of the PIF motif by PHLPP1/2 results in reduced stability and increased degradation of PKC. This is countered by autophosphorylation of the PIF motif, but mTORC2 might also contribute. | ||
| SGK1_HUMAN | 418 | 423 | Binary | Physicochemical compatibility | Phosphorylation of S422 by Serine/threonine-protein kinase mTOR (MTOR) (as part of mTORC2 complex) in the PIF pocket-binding motif of Serine/threonine-protein kinase Sgk1 (SGK1) induces intramolecular binding and kinase cis-activation. | ||
| SCH9_YEAST | 733 | 738 | Binary | Physicochemical compatibility | Phosphorylation of T737 by Serine/threonine-protein kinase TOR1 (TOR1) in the PIF pocket-binding motif of Serine/threonine-protein kinase SCH9 (SCH9) induces intramolecular binding and kinase cis-activation. | ||
| KS6A3_MOUSE | 382 | 387 | Binary | Physicochemical compatibility | Auto-phosphorylation of S386 in the PIF pocket-binding motif of Ribosomal protein S6 kinase alpha-3 (Rps6ka3) induces intramolecular binding and kinase cis-activation. | ||
| AKT2_HUMAN | 470 | 475 | Binary | Physicochemical compatibility | Phosphorylation of S474 in the PIF pocket-binding motif of RAC-beta serine/threonine-protein kinase (AKT2) induces intramolecular binding and kinase cis-activation. | ||
| KS6B1_RAT | 408 | 413 | Binary | Physicochemical compatibility | Phosphorylation of T412 in the PIF pocket-binding motif of Ribosomal protein S6 kinase beta-1 (Rps6kb1) induces intramolecular binding and kinase cis-activation. | ||
| ROCK1_HUMAN | 394 | 399 | Binary | Physicochemical compatibility | Phosphorylation of T398 in the PIF pocket-binding motif of Rho-associated protein kinase 1 (ROCK1) induces intramolecular binding and kinase cis-activation. | ||
| SGK3_HUMAN | 482 | 487 | Binary | Physicochemical compatibility | Phosphorylation of S486 in the PIF pocket-binding motif of Serine/threonine-protein kinase Sgk3 (SGK3) induces intramolecular binding and kinase cis-activation. | ||
| SGK3_MOUSE | 482 | 487 | Binary | Physicochemical compatibility | Phosphorylation of S486 in the PIF pocket-binding motif of Serine/threonine-protein kinase Sgk3 (Sgk3) induces intramolecular binding and kinase cis-activation. | ||
MOD_CDK - | |||||||
| MK67I_HUMAN | 235 | 241 | Specificity | Altered binding specificity | Phosphorylation of T238 of MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) by Cyclin-dependent kinase 1 (CDK1) primes for phosphorylation of T234 by Glycogen synthase kinase-3 beta (GSK3B), which primes for phosphorylation of S230 by GSK3B. Triple-phosphorylated hNIFK (MKI67IP) binds strongly to Antigen KI-67 (MKI67). | ||
MOD_CDK_1 - Substrate motif for phosphorylation by CDK | |||||||
| CDN1B_HUMAN | 184 | 190 | Pre‑assembly | Composite binding site formation | Binding of Cyclin-dependent kinase inhibitor 1B (CDKN1B) (p27) to the SCF-Skp2 ubiquitin ligase complex requires phosphorylation of p27 (CDKN1B) at T187, and association of the F-box protein S-phase kinase-associated protein 2 (SKP2) with the regulatory Cyclin-dependent kinases regulatory subunit 1 (CKS1B). SKP2 and CKS1B together generate a composite binding site for p27 (CDKN1B). While some residues, including the phosphorylated T187, bind to CKS1B and others to SKP2, the E185 makes contact with residues of both CKS1B and SKP2. | ||
| CDN1C_HUMAN | 307 | 313 | Pre‑assembly | Composite binding site formation | Binding of Cyclin-dependent kinase inhibitor 1C (CDKN1C) (p57) to the SCF-Skp2 ubiquitin ligase complex requires phosphorylation of p57 (CDKN1C) at T310, and association of the F-box protein S-phase kinase-associated protein 2 (SKP2) with the regulatory Cyclin-dependent kinases regulatory subunit 1 (CKS1B). SKP2 and CKS1B together generate a composite binding site for p57 (CDKN1C). | ||
| CDN1C_MOUSE | 339 | 345 | Pre‑assembly | Composite binding site formation | Binding of Cyclin-dependent kinase inhibitor 1C (Cdkn1c) (p57) to the SCF-Skp2 ubiquitin ligase complex requires phosphorylation of p57 (Cdkn1c) at T342, and association of the F-box protein S-phase kinase-associated protein 2 (SKP2) with the regulatory Cyclin-dependent kinases regulatory subunit 1 (CKS1B). SKP2 and CKS1B together generate a composite binding site for p57 (Cdkn1c). | ||
| ODFP2_HUMAN | 793 | 799 | Binary | Pre‑translational | Alternative splicing removes the cyclin-dependent kinase (CDK) phosphorylation motif of Isoform Cenexin 1 of Outer dense fiber protein 2 (ODF2), abrogating binding to Cyclin-dependent kinase 1 (CDK1). This phosphorylation is required for the recruitment of Serine/threonine-protein kinase PLK1 (PLK1). The C-terminal extension of Isoform Cenexin 1 of Outer dense fiber protein 2 (ODF2) has the ability to distinctly localise to mother centriole whereas the splice variant (e.g. Isoform Cenexin 1 of Outer dense fiber protein 2 (ODF2)), which does not have this extension, permits ODF2 to associate with sperm tail. | ||
MOD_CK1_1 - CK1 phosphorylation site | |||||||
| YAP1_HUMAN | 381 | 387 | Specificity | Altered binding specificity | Phosphorylation of Yorkie homolog (YAP1) at S381 by Serine/threonine-protein kinase LATS1 (LATS1) (a key regulator of the Hippo Pathway) primes the sequence for phosphorylation by Casein kinase I isoform epsilon (CSNK1E) at S384 and S387. This targets YAP1 to the SCF ubiqutin ligase complex, F-box/WD repeat-containing protein 1A (BTRC), which marks is YAP1 for subsequent degradation by the proteasomal system. N.B. Serine/threonine-protein kinase LATS2 (LATS2) can replace LATS1 and Casein kinase I isoform delta (CSNK1D) can replace CSNK1E | ||
| YAP1_HUMAN | 384 | 390 | Specificity | Altered binding specificity | Phosphorylation of Yorkie homolog (YAP1) at S381 by Serine/threonine-protein kinase LATS1 (LATS1) (a key regulator of the Hippo Pathway) primes the sequence for phosphorylation by Casein kinase I isoform epsilon (CSNK1E) at S384 and S387. This targets YAP1 to the SCF ubiqutin ligase complex, F-box/WD repeat-containing protein 1A (BTRC), which marks is YAP1 for subsequent degradation by the proteasomal system. N.B. Serine/threonine-protein kinase LATS2 (LATS2) can replace LATS1 and Casein kinase I isoform delta (CSNK1D) can replace CSNK1E | ||
MOD_GSK3_1 - GSK3 phosphorylation recognition site | |||||||
| NFAC1_HUMAN | 287 | 294 | Binary | Physicochemical compatibility | Phosphorylation of S294 adjacent to the NLS of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) by cAMP subfamily primes Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) for subsequent phosphorylation by Glycogen synthase kinase-3 beta (GSK3B), which results in inhibition of nuclear import of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). | ||
| NFAC1_HUMAN | 238 | 245 | Binary | Physicochemical compatibility | Phosphorylation of S245 adjacent to the NLS of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) by cAMP subfamily primes Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1) for subsequent phosphorylation by Glycogen synthase kinase-3 beta (GSK3B), which results in inhibition of nuclear import of Nuclear factor of activated T-cells, cytoplasmic 1 (NFATC1). | ||
| MYC_HUMAN | 55 | 62 | Binary | Physicochemical compatibility | Phosphorylation of Myc proto-oncogene protein (MYC) at S62 primes the protein for phosphorylation at T58 by Glycogen synthase kinase-3 beta (GSK3B). | ||
| P53_HUMAN | 30 | 37 | Binary | Physicochemical compatibility | Phosphorylation of Cellular tumor antigen p53 (TP53) at S37 primes the protein for phosphorylation at S33 by Glycogen synthase kinase-3 beta (GSK3B). | ||
| JUN_HUMAN | 236 | 243 | Binary | Physicochemical compatibility | Phosphorylation of Transcription factor AP-1 (JUN) at S243 primes the protein for phosphorylation at T239 by Glycogen synthase kinase-3 beta (GSK3B). | ||
| CCNE1_HUMAN | 392 | 399 | Binary | Physicochemical compatibility | Phosphorylation of G1/S-specific cyclin-E1 (CCNE1) at S399 by Cyclin-dependent kinase 2 (CDK2) primes the protein for subsequent phosphorylation at T395 by Glycogen synthase kinase-3 beta (GSK3B). | ||
| ATX3_HUMAN | 253 | 260 | Binary | Physicochemical compatibility | Phosphorylation of Ataxin-3 (ATXN3) at S260 primes the protein for subsequent phosphorylation at S256 by Glycogen synthase kinase-3 beta (GSK3B). | ||
| CCNE1_HUMAN | 377 | 384 | Specificity | Altered binding specificity | Phosphorylation of Isoform E-S of G1/S-specific cyclin-E1 (CCNE1) at S384 by CDK2 primes CCNE1 for phosphorylation by Glycogen synthase kinase-3 beta (GSK3B) at T380, which creates a recognition site for F box proteins of the SCF ubiquitin ligase complex (F-box/WD repeat-containing protein 7 (FBXW7)) that target CCNE1 for degradation. | ||
| SMAD3_HUMAN | 201 | 208 | Specificity | Altered binding specificity | 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. | ||
| FGD1_HUMAN | 280 | 287 | Specificity | Altered binding specificity | Phosphorylation of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1), a GEF for CDC42 small effector protein 2 (CDC42SE2), by Glycogen synthase kinase-3 beta (GSK3B) targets FGD1 to the SCF ubiquitin ligase complex, F-box/WD repeat-containing protein 1A (BTRC), which marks FGD1 for degradation. | ||
| FGD3_HUMAN | 77 | 84 | Specificity | Altered binding specificity | Phosphorylation of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3), a GEF for CDC42 small effector protein 2 (CDC42SE2), by Glycogen synthase kinase-3 beta (GSK3B) targets FGD3 to the SCF ubiquitin ligase complex, F-box/WD repeat-containing protein 1A (BTRC), which marks FGD3 for degradation. | ||
| FGD3_HUMAN | 73 | 80 | Specificity | Altered binding specificity | Phosphorylation of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3), a GEF for CDC42 small effector protein 2 (CDC42SE2), by Glycogen synthase kinase-3 beta (GSK3B) targets FGD3 to the SCF ubiquitin ligase complex, F-box/WD repeat-containing protein 1A (BTRC), which marks FGD3 for degradation. | ||
| MK67I_HUMAN | 231 | 238 | Specificity | Altered binding specificity | Phosphorylation of T238 of MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) by Cyclin-dependent kinase 1 (CDK1) primes for phosphorylation of T234 by Glycogen synthase kinase-3 beta (GSK3B), which primes for phosphorylation of S230 by GSK3B. Triple-phosphorylated hNIFK (MKI67IP) binds strongly to Antigen KI-67 (MKI67). | ||
| MK67I_HUMAN | 227 | 234 | Specificity | Altered binding specificity | Phosphorylation of T238 of MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) by Cyclin-dependent kinase 1 (CDK1) primes for phosphorylation of T234 by Glycogen synthase kinase-3 beta (GSK3B), which primes for phosphorylation of S230 by GSK3B. Triple-phosphorylated hNIFK (MKI67IP) binds strongly to Antigen KI-67 (MKI67). | ||
| MYC_HUMAN | 55 | 62 | Specificity | Altered binding specificity | 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. | ||
| JUN_HUMAN | 236 | 243 | Specificity | Altered binding specificity | 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. | ||
| CCNE1_HUMAN | 392 | 399 | Specificity | Altered binding specificity | Phosphorylation of G1/S-specific cyclin-E1 (CCNE1) at S399 generates a docking site for Glycogen synthase kinase-3 beta (GSK3B). Subsequent phosphorylation of CCNE1 by Glycogen synthase kinase-3 beta (GSK3B) at T395 switches the specificity of CCNE1 to the F-box/WD repeat-containing protein 7 (FBXW7), which recruits CCNE1 to the SCF ubiquitin ligase complex to mark CCNE1 for degradation. | ||
| SRBP1_HUMAN | 422 | 430 | Specificity | Altered binding specificity | Phosphorylation of SREBP-1 (Sterol regulatory element-binding protein 1 (SREBF1)) at S430 generates a docking site for Glycogen synthase kinase-3 beta (GSK3B). Subsequent phosphorylation of SREBP-1 (SREBF1) by GSK3B at T426 switches the specificity of SREBP-1 (SREBF1) to the F-box/WD repeat-containing protein 7 (FBXW7), which recruits SREBP-1 (SREBF1) to the SCF ubiquitin ligase complex to mark SREBP-1 (SREBF1) for degradation. | ||
| CTNB1_HUMAN | 34 | 41 | Specificity | Altered binding specificity | Phosphorylation of Catenin beta-1 (CTNNB1) at T41 generates a docking site for Glycogen synthase kinase-3 beta (GSK3B), which then phosphorylates S37, thereby generating a new docking site for GSK3B. Subsequent phosphorylation of S33 by GSK3B switches the specificity of CTNNB1 to the F-box/WD repeat-containing protein 1A (BTRC), which recruits CTNNB1 to the SCF ubiquitin ligase complex. | ||
| CTNB1_HUMAN | 30 | 37 | Specificity | Altered binding specificity | Phosphorylation of Catenin beta-1 (CTNNB1) at T41 generates a docking site for Glycogen synthase kinase-3 beta (GSK3B), which then phosphorylates S37, thereby generating a new docking site for GSK3B. Subsequent phosphorylation of S33 by GSK3B switches the specificity of CTNNB1 to the F-box/WD repeat-containing protein 1A (BTRC), which recruits CTNNB1 to the SCF ubiquitin ligase complex. | ||
| SNAI1_HUMAN | 93 | 100 | Specificity | Altered binding specificity | Phosphorylation of Zinc finger protein SNAI1 (SNAI1) at S100 generates a docking site for Glycogen synthase kinase-3 beta (GSK3B). Subsequent phosphorylation of S96 by GSK3B targets Zinc finger protein SNAI1 (SNAI1) to the SCF ubiquitin ligase complexes F-box/WD repeat-containing protein 1A (BTRC), which marks it for degradation. | ||
| ESR2_HUMAN | 5 | 12 | Binary | Physicochemical compatibility | The GSK3-beta binding site at S12 in Estrogen receptor beta (ESR2) is primed by (most likely) RAC-alpha serine/threonine-protein kinase (AKT1). This enhances the binding of SUMO-conjugating enzyme UBC9 (UBE2I) at the adjacent Sumoylation site. This site is also primed at S6 (most likely) by AKT1. The addition of SUMO at K4 stabilises ESR2 as it prevents the ubiquitination at K4 (see switch details | ||
MOD_LATS_1 - The LATS phosphorylation motif is recognised by the LATS kinases for Ser/Thr phosphorylation. Substrates are often found toward the end of the Hippo signalling pathway. | |||||||
| YAP1_HUMAN | 376 | 382 | Specificity | Altered binding specificity | Phosphorylation of Yorkie homolog (YAP1) at S381 by Serine/threonine-protein kinase LATS1 (LATS1) (a key regulator of the Hippo Pathway) primes the sequence for phosphorylation by Casein kinase I isoform epsilon (CSNK1E) at S384 and S387. This targets YAP1 to the SCF ubiqutin ligase complex, F-box/WD repeat-containing protein 1A (BTRC), which marks is YAP1 for subsequent degradation by the proteasomal system. N.B. Serine/threonine-protein kinase LATS2 (LATS2) can replace LATS1 and Casein kinase I isoform delta (CSNK1D) can replace CSNK1E | ||
MOD_PKA_1 - Main preference for PKA-type AGC kinase phosphorylation. | |||||||
| SYN_DROME | 3 | 9 | Binary | Pre‑translational | RNA editing removes the degron motif of Synapsin (Syn), abrogating binding to cAMP-dependent protein kinase catalytic subunit (Pka-C1). A genomic version of the protein sequence contains a canonical PKA-recognition motif that is highly conserved, however in Drosophilia, in all except the embryo sequences this sequence was RNA-edited to RGFS (from RRFS). | ||
MOD_PKA_2 - Secondary preference for PKA-type AGC kinase phosphorylation. | |||||||
| SPTB2_HUMAN | 2157 | 2162 | Binary | Pre‑translational | Alternative splicing removes the PKA-binding motif of Isoform Short of Spectrin beta chain, brain 1 (SPTBN1), abrogating binding to cAMP-dependent protein kinase catalytic subunit alpha (PRKACA). The phosphorylation of the short C-terminal betaII-spectrin (also known as Isoform Short of Spectrin beta chain, brain 1 (SPTBN1)) by PKA is important in allowing neuritogenesis. | ||
MOD_ProDKin_1 - Proline-Directed Kinase (e.g. MAPK) phosphorylation site in higher eukaryotes. | |||||||
| MYC_HUMAN | 59 | 65 | Specificity | Altered binding specificity | 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. | ||