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| Aldosterone-regulated sodium reabsorption | Cell cycle | Endocytosis |
| ErbB signaling pathway | Wnt signaling pathway |
| Motif | Protein | Start | End | Switch Type | Switch Subtype | Switch description | Information | Evidence |
Aldosterone-regulated sodium reabsorption (KEGG - hsa04960) | ||||||||
| LIG_WW_1 | SCNNG_HUMAN | 624 | 627 | Specificity | Domain hiding | Phosphorylation of Isoform Nedd4-2a of E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) by Serine/threonine-protein kinase Sgk1 (SGK1) induces binding to 14-3-3 protein eta (YWHAH). This inhibits (whether allosterically or sterically is not known) interactions of NEDD4L via its WW domains with the PY motif in Amiloride-sensitive sodium channel subunit gamma (SCNN1G) (ENaC). As a result, ENaC does not get degraded and ENaC-mediated Na+ currents increase. | Inferred | |
Cell cycle (KEGG - hsa04110) | ||||||||
| LIG_WW_1 | SMAD3_HUMAN | 181 | 184 | 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. | Inferred | |
Endocytosis (KEGG - hsa04144) | ||||||||
| LIG_WW_1 | SMAD3_HUMAN | 181 | 184 | 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. | Inferred | |
| LIG_WW_1 | ERBB4_HUMAN | 1053 | 1056 | Specificity | Altered binding specificity | Phosphorylation-dependent binding of Receptor tyrosine-protein kinase erbB-4 (ERBB4) to the SH2 domains of Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1) results in signaling activation, while binding to the WW domains of E3 ubiquitin-protein ligase Itchy homolog (ITCH) to unphopshorylated ERBB4 results in ubiquitylation, endocytosis and ultimately degradation of ERBB4. | Inferred | |
| LIG_WW_1 | ERBB4_HUMAN | 1053 | 1056 | Binary | Pre‑translational | Alternative splicing removes the WW-binding motif of Receptor tyrosine-protein kinase erbB-4 (ERBB4), abrogating binding to E3 ubiquitin-protein ligase Itchy homolog (ITCH). The presence of a WW-binding motif mediates ERBB4 mono-ubiquitination and endocytosis by the WW domain-containing HECT-type E3 ubiquitin ligase ITCH. | Inferred | |
| LIG_WW_1 | SMAD3_HUMAN | 181 | 184 | Avidity‑sensing | 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 the 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. Dual phosphorylation of the two NEDD4L-binding sites mediates high-avidity binding of two WW domains of NEDD4L to SMAD3. See also switch details and switch details. | Inferred | ||
| LIG_WW_1 | ERBB4_HUMAN | 1053 | 1056 | Binary | Pre‑translational | Alternative splicing removes the WW-binding motif of Receptor tyrosine-protein kinase erbB-4 (ERBB4), abrogating binding to E3 ubiquitin-protein ligase Itchy homolog (ITCH). The presence of a WW-binding motif mediates ERBB4 mono-ubiquitination and endocytosis by the WW domain-containing HECT-type E3 ubiquitin ligase ITCH. | Inferred | |
ErbB signaling pathway (KEGG - hsa04012) | ||||||||
| LIG_WW_1 | ERBB4_HUMAN | 1053 | 1056 | Specificity | Altered binding specificity | Phosphorylation-dependent binding of Receptor tyrosine-protein kinase erbB-4 (ERBB4) to the SH2 domains of Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1) results in signaling activation, while binding to the WW domains of E3 ubiquitin-protein ligase Itchy homolog (ITCH) to unphopshorylated ERBB4 results in ubiquitylation, endocytosis and ultimately degradation of ERBB4. | Inferred | |
Wnt signaling pathway (KEGG - hsa04310) | ||||||||
| LIG_WW_1 | SMAD3_HUMAN | 181 | 184 | 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. | Inferred | |