GNAQ pathways in port-wine stain (WP5437)
Homo sapiens
Port-wine stains are caused by somatic, mosaic mutations in the GNAQ gene. The pathogenic variant is usually a p.R183Q (c.G548A) mutation in guanine nucleotide binding protein alpha subunit q (GNAQ), primarily expressed in endothelial cells. This pathway shows predicted downstream targets of GNAQ that have been implicated in cell proliferation and survival, which leads to angiogenesis and capillary overgrowth. The resulting capillary malformation (CM) causes visibly pink, dark red, or purple discoloration of skin. Such "port wine stain" (PWS) of the skin is usually apparent at birth. It has a prevalence of 3-5 children per 1000 live births. PWS lesions, also known as nevus flammeus, are permanent but treatable by laser and topical therapies. In approximately 1 in 50,000 newborns, PWS is associated with Sturge-Weber syndrome (SWS), a more serious condition that has symptoms including glaucoma, seizures, and developmental delay. This diagram is based on figure 2 in Van Trigt et al. (2022).
Authors
Eric Weitz , Alex Pico , Egon Willighagen , and Martina Summer-KutmonActivity
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Organisms
Homo sapiensCommunities
Annotations
Pathway Ontology
disease pathway signaling pathwayCell Type Ontology
endothelial cellDisease Ontology
Sturge-Weber syndrome vascular disease capillary disease| Label | Type | Compact URI | Comment |
|---|---|---|---|
| GNAQ | GeneProduct | ensembl:ENSG00000156052 | |
| G-gamma | GeneProduct | interpro:IPR036284 | |
| G-beta | GeneProduct | interpro:IPR016346 | |
| PI3K | GeneProduct | ensembl:ENSG00000121879 | |
| TRIO | GeneProduct | ensembl:ENSG00000038382 | |
| PDPK1 | GeneProduct | ensembl:ENSG00000152256 | |
| AKT | GeneProduct | ensembl:ENSG00000142208 | |
| MTOR | GeneProduct | ensembl:ENSG00000198793 | |
| NFKB1 | GeneProduct | ensembl:ENSG00000109320 | |
| RAF1 | GeneProduct | ensembl:ENSG00000132155 | |
| MAP2K1 | GeneProduct | ensembl:ENSG00000169032 | 'MEK' is an general enzyme that can be encoded by any of 7 genes, per Wikipedia: MAP2K1 (a.k.a. MEK1) MAP2K2 (a.k.a. MEK2) MAP2K3 (a.k.a. MKK3) MAP2K4 (a.k.a. MKK4) MAP2K5 (a.k.a. MKK5) MAP2K6 (a.k.a. MKK6) MAP2K7 (a.k.a. MKK7) Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| MAPK1 | GeneProduct | ensembl:ENSG00000100030 | Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| RHOA | GeneProduct | ensembl:ENSG00000067560 | https://doi.org/10.3390/cancers14133066 notes: 'Feng et al. demonstrated that the GNAQ oncogene is able to control the Hippo pathway through a cytoplasmic protein tyrosine kinase called focal adhesion kinase (FAK). They detailed that Gαq activates FAK through a non-canonical TRIO-RhoA signalling pathway' |
| RAC1 | GeneProduct | ensembl:ENSG00000136238 | |
| AMOT | GeneProduct | ensembl:ENSG00000126016 | |
| YAP1 | GeneProduct | ensembl:ENSG00000137693 | |
| MAP2K2 | GeneProduct | ensembl:ENSG00000126934 | 'MEK' is an general enzyme that can be encoded by any of 7 genes, per Wikipedia: MAP2K1 (a.k.a. MEK1) MAP2K2 (a.k.a. MEK2) MAP2K3 (a.k.a. MKK3) MAP2K4 (a.k.a. MKK4) MAP2K5 (a.k.a. MKK5) MAP2K6 (a.k.a. MKK6) MAP2K7 (a.k.a. MKK7) Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| MAP2K3 | GeneProduct | ensembl:ENSG00000034152 | 'MEK' is an general enzyme that can be encoded by any of 7 genes, per Wikipedia: MAP2K1 (a.k.a. MEK1) MAP2K2 (a.k.a. MEK2) MAP2K3 (a.k.a. MKK3) MAP2K4 (a.k.a. MKK4) MAP2K5 (a.k.a. MKK5) MAP2K6 (a.k.a. MKK6) MAP2K7 (a.k.a. MKK7) Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| MAP2K4 | GeneProduct | ensembl:ENSG00000065559 | 'MEK' is an general enzyme that can be encoded by any of 7 genes, per Wikipedia: MAP2K1 (a.k.a. MEK1) MAP2K2 (a.k.a. MEK2) MAP2K3 (a.k.a. MKK3) MAP2K4 (a.k.a. MKK4) MAP2K5 (a.k.a. MKK5) MAP2K6 (a.k.a. MKK6) MAP2K7 (a.k.a. MKK7) Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| MAP2K5 | GeneProduct | ensembl:ENSG00000137764 | 'MEK' is an general enzyme that can be encoded by any of 7 genes, per Wikipedia: MAP2K1 (a.k.a. MEK1) MAP2K2 (a.k.a. MEK2) MAP2K3 (a.k.a. MKK3) MAP2K4 (a.k.a. MKK4) MAP2K5 (a.k.a. MKK5) MAP2K6 (a.k.a. MKK6) MAP2K7 (a.k.a. MKK7) Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| MAP2K6 | GeneProduct | ensembl:ENSG00000108984 | 'MEK' is an general enzyme that can be encoded by any of 7 genes, per Wikipedia: MAP2K1 (a.k.a. MEK1) MAP2K2 (a.k.a. MEK2) MAP2K3 (a.k.a. MKK3) MAP2K4 (a.k.a. MKK4) MAP2K5 (a.k.a. MKK5) MAP2K6 (a.k.a. MKK6) MAP2K7 (a.k.a. MKK7) Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| MAP2K7 | GeneProduct | ensembl:ENSG00000076984 | 'MEK' is an general enzyme that can be encoded by any of 7 genes, per Wikipedia: MAP2K1 (a.k.a. MEK1) MAP2K2 (a.k.a. MEK2) MAP2K3 (a.k.a. MKK3) MAP2K4 (a.k.a. MKK4) MAP2K5 (a.k.a. MKK5) MAP2K6 (a.k.a. MKK6) MAP2K7 (a.k.a. MKK7) Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
| MAPK3 | GeneProduct | ensembl:ENSG00000102882 | Literature notes: 'No specific YAP inhibitors are currently in clinical use, however, Truong et al. demonstrated that combined therapy with trametinib MEK1/2 inhibition and the lysosome inhibitor chloroquine increased cytotoxicity while indirectly decreasing YAP nuclear localization and transcriptional activity (Feng et al., 2019; Truong et al., 2020). Other groups have proposed GNAQ overactivation of ERK1/2 or MEK1/2 as a driver of UM, but inhibitors of this pathway alone are typically insufficient to stop progression and the degree of MAPK activation is widely heterogeneous within tumor sites' |
References
- GNAQ mutations drive port wine birthmark-associated Sturge-Weber syndrome: A review of pathobiology, therapies, and current models. Van Trigt WK, Kelly KM, Hughes CCW. Front Hum Neurosci. 2022 Nov 3;16:1006027. PubMed Europe PMC Scholia