Molecule Information

General Information of the Molecule (ID: Mol01841)

• Name: Guanine nucleotide-binding protein alpha-q (GNAQ) ,Homo sapiens
• Synonyms: Guanine nucleotide-binding protein G(q) subunit alpha; Guanine nucleotide-binding protein alpha-q; GNAQ; GAQ
• Molecule Type: Protein
• Gene Name: GNAQ
• Gene ID: 2776
• Location: chr9:77,716,097-78,031,811[-]
• Sequence:
  MTLESIMACCLSEEAKEARRINDEIERQLRRDKRDARRELKLLLLGTGESGKSTFIKQMR
  IIHGSGYSDEDKRGFTKLVYQNIFTAMQAMIRAMDTLKIPYKYEHNKAHAQLVREVDVEK
  VSAFENPYVDAIKSLWNDPGIQECYDRRREYQLSDSTKYYLNDLDRVADPAYLPTQQDVL
  RVRVPTTGIIEYPFDLQSVIFRMVDVGGQRSERRKWIHCFENVTSIMFLVALSEYDQVLV
  ESDNENRMEESKALFRTIITYPWFQNSSVILFLNKKDLLEEKIMYSHLVDYFPEYDGPQR
  DAQAAREFILKMFVDLNPDSDKIIYSHFTCATDTENIRFVFAAVKDTILQLNLKEYNLV
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Regulates B-cell selection and survival and is required to prevent B-cell-dependent autoimmunity. Regulates chemotaxis of BM-derived neutrophils and dendritic cells (in vitro) (By similarity). Transduces FFAR4 signaling in response to long-chain fatty acids (LCFAs).
• Uniprot ID: GNAQ_HUMAN
• Ensembl ID: ENSG00000156052
• HGNC ID: HGNC:4390

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Verteporfin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [1]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Verteporfin
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vivo Model: Nude mouse PDX model; Mus musculus

Clinical Trial Drug(s) 4 drug(s) in total

Enzastaurin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [2]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Enzastaurin
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ocm3 cells; Skin; Homo sapiens (Human); CVCL_6937
• In Vitro Model: Ocm1 cells; Hypodermis; Homo sapiens (Human); CVCL_6934
• In Vitro Model: Mum2C cells; Hypodermis; Homo sapiens (Human); CVCL_3448
• In Vitro Model: Mum2B cells; Uveal melanoma; Homo sapiens (Human); CVCL_3447
• In Vitro Model: M619 cells; Skin; Homo sapiens (Human); CVCL_8472
• In Vitro Model: C918 cells; Skin; Homo sapiens (Human); CVCL_8471
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.Q209P (c.626A>C) in gene GNAQ cause the sensitivity of Enzastaurin by unusual activation of pro-survival pathway

Disease Class: Uveal melanoma [2]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Enzastaurin
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ocm3 cells; Skin; Homo sapiens (Human); CVCL_6937
• In Vitro Model: Ocm1 cells; Hypodermis; Homo sapiens (Human); CVCL_6934
• In Vitro Model: Mum2C cells; Hypodermis; Homo sapiens (Human); CVCL_3448
• In Vitro Model: Mum2B cells; Uveal melanoma; Homo sapiens (Human); CVCL_3447
• In Vitro Model: M619 cells; Skin; Homo sapiens (Human); CVCL_8472
• In Vitro Model: C918 cells; Skin; Homo sapiens (Human); CVCL_8471
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of Enzastaurin by unusual activation of pro-survival pathway

Refametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [3]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Refametinib
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of Refametinib by aberration of the drug's therapeutic target

Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [4]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Omm13 cells; N.A.; .; N.A.
• In Vitro Model: Mel270 cells; Skin; Homo sapiens (Human); CVCL_C302
• In Vitro Model: Mel202 cells; Eye; Homo sapiens (Human); CVCL_C301
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway

Disease Class: Uveal melanoma [4]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Selumetinib
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Omm13 cells; N.A.; .; N.A.
• In Vitro Model: Mel270 cells; Skin; Homo sapiens (Human); CVCL_C302
• In Vitro Model: Mel202 cells; Eye; Homo sapiens (Human); CVCL_C301
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.Q209P (c.626A>C) in gene GNAQ cause the sensitivity of Selumetinib by unusual activation of pro-survival pathway

PLX4720

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Melanoma [5]

• Resistant Disease: Melanoma [ICD-11: 2C30.0]
• Resistant Drug: PLX4720
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Experiment for Molecule Alteration: Sanger sequencing assay; SNP array; qPCR
• Experiment for Drug Resistance: CellTiter-Glo assay

Preclinical Drug(s) 4 drug(s) in total

FR900359

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [6]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: FR900359
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: UM002B cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Omm13 cells; N.A.; .; N.A.
• In Vitro Model: Ocm3 cells; Skin; Homo sapiens (Human); CVCL_6937
• In Vitro Model: 92-1 cells; Bladder; Homo sapiens (Human); CVCL_W909
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blotting analysis

Disease Class: Uveal melanoma [6]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: FR900359
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: UM002B cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Omm13 cells; N.A.; .; N.A.
• In Vitro Model: Ocm3 cells; Skin; Homo sapiens (Human); CVCL_6937
• In Vitro Model: 92-1 cells; Bladder; Homo sapiens (Human); CVCL_W909
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blotting analysis

NAV-2729

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [7]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: NAV-2729
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mel921 cells; N.A.; .; N.A.
• In Vitro Model: Mel202 cells; Eye; Homo sapiens (Human); CVCL_C301
• In Vivo Model: Nude mouse PDX model; Mus musculus
• Mechanism Description: Activating mutations in Galphaq proteins, which form the a subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Galphaq signaling to induce all of these downstream pathways as well as beta-catenin signaling. ARF6 activates these diverse pathways through a common mechanism-the trafficking of GNAQ and beta-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small molecule reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway.

Omipalisib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [8]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Omipalisib/Trametinib
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-blue assay
• Mechanism Description: The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of Omipalisib + Trametinib by unusual activation of pro-survival pathway

Disease Class: Uveal melanoma [8]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Omipalisib/Trametinib
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell Titer-blue assay
• Mechanism Description: The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of Omipalisib + Trametinib by unusual activation of pro-survival pathway

Sotrastaurin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [9]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Sotrastaurin
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Omm13 cells; N.A.; .; N.A.
• In Vitro Model: Ocm3 cells; Skin; Homo sapiens (Human); CVCL_6937
• In Vitro Model: Ocm1 cells; Hypodermis; Homo sapiens (Human); CVCL_6934
• In Vitro Model: Mel285 cells; Skin; Homo sapiens (Human); CVCL_C303
• In Vitro Model: Mel202 cells; Eye; Homo sapiens (Human); CVCL_C301
• In Vitro Model: C918 cells; Skin; Homo sapiens (Human); CVCL_8471
• In Vitro Model: 92-1 cells; Bladder; Homo sapiens (Human); CVCL_W909
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: V-FITC assay
• Mechanism Description: The missense mutation p.Q209P (c.626A>C) in gene GNAQ cause the sensitivity of Sotrastaurin by unusual activation of pro-survival pathway

Disease Class: Uveal melanoma [10]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: Sotrastaurin
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: OMM-GN11; N.A.; Mus musculus (Mouse); N.A.
• In Vitro Model: OMM13; N.A.; .; N.A.
• In Vitro Model: Mel202; Eye; Homo sapiens (Human); CVCL_C301
• In Vitro Model: GNAQ cells; N.A.; .; N.A.
• In Vitro Model: Mel270 cells; Skin; Homo sapiens (Human); CVCL_C302
• In Vitro Model: GNA11 cells; N.A.; .; N.A.
• In Vitro Model: UPMD-1 cells; Skin; Homo sapiens (Human); CVCL_C297
• In Vitro Model: 92-1 cells; Bladder; Homo sapiens (Human); CVCL_W909
• In Vitro Model: Mel202; Eye; Homo sapiens (Human); CVCL_C301
• In Vivo Model: C57/BL6 mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell proliferation assay

Investigative Drug(s) 2 drug(s) in total

TAK-733

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [11]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: TAK-733
• Molecule Alteration: Missense mutation; p.Q209P (c.626A>C)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Wn1366 cells; Skin; Homo sapiens (Human); CVCL_6789
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: SBCL2 cells; Skin; Homo sapiens (Human); CVCL_D732
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.Q209P (c.626A>C) in gene GNAQ cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway

Disease Class: Uveal melanoma [11]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: TAK-733
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Wn1366 cells; Skin; Homo sapiens (Human); CVCL_6789
• In Vitro Model: SkMEL28 cells; Skin; Homo sapiens (Human); CVCL_0526
• In Vitro Model: SBCL2 cells; Skin; Homo sapiens (Human); CVCL_D732
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of TAK-733 by unusual activation of pro-survival pathway

U0126

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Uveal melanoma [12]

• Sensitive Disease: Uveal melanoma [ICD-11: 2D0Y.0]
• Sensitive Drug: U0126
• Molecule Alteration: Missense mutation; p.Q209L (c.626A>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Eyeball; .
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: CyQUANT Cell (Invitrogen) proliferation assay
• Mechanism Description: The missense mutation p.Q209L (c.626A>T) in gene GNAQ cause the sensitivity of U0126 by unusual activation of pro-survival pathway

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Melanoma [ICD-11: 2C30]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Skin
• The Specified Disease: Melanoma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.56E-01; Fold-change: 2.39E-01; Z-score: 3.16E-01

References

• Ref 1: YAP inhibition blocks uveal melanogenesis driven by GNAQ or GNA11 mutationsMol Cell Oncol. 2014 Dec 1;2(1):e970957. doi: 10.4161/23723548.2014.970957. eCollection 2015 Jan-Mar.
• Ref 2: The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanomaPLoS One. 2012;7(1):e29622. doi: 10.1371/journal.pone.0029622. Epub 2012 Jan 12.
• Ref 3: Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancerClin Cancer Res. 2013 Mar 1;19(5):1232-43. doi: 10.1158/1078-0432.CCR-12-3529. Epub 2013 Feb 22.
• Ref 4: Identification of unique MEK-dependent genes in GNAQ mutant uveal melanoma involved in cell growth, tumor cell invasion, and MEK resistanceClin Cancer Res. 2012 Jul 1;18(13):3552-61. doi: 10.1158/1078-0432.CCR-11-3086. Epub 2012 May 1.
• Ref 5: Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibitionAnn Oncol. 2014 May;25(5):959-67. doi: 10.1093/annonc/mdu049. Epub 2014 Feb 6.
• Ref 6: Effects of Oncogenic GAlpha(q) and GAlpha(11) Inhibition by FR900359 in Uveal MelanomaMol Cancer Res. 2019 Apr;17(4):963-973. doi: 10.1158/1541-7786.MCR-18-0574. Epub 2018 Dec 19.
• Ref 7: ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal MelanomaCancer Cell. 2016 Jun 13;29(6):889-904. doi: 10.1016/j.ccell.2016.04.015. Epub 2016 Jun 2.
• Ref 8: Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent mannerClin Cancer Res. 2012 Aug 15;18(16):4345-55. doi: 10.1158/1078-0432.CCR-11-3227. Epub 2012 Jun 25.
• Ref 9: Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-kB pathwaysMol Cancer Ther. 2012 Sep;11(9):1905-14. doi: 10.1158/1535-7163.MCT-12-0121. Epub 2012 May 31.
• Ref 10: Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutationsOncogene. 2014 Sep 25;33(39):4724-34. doi: 10.1038/onc.2013.418. Epub 2013 Oct 21.
• Ref 11: Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell linesMol Cancer. 2012 Apr 19;11:22. doi: 10.1186/1476-4598-11-22.
• Ref 12: Frequent somatic mutations of GNAQ in uveal melanoma and blue naeviNature. 2009 Jan 29;457(7229):599-602. doi: 10.1038/nature07586. Epub 2008 Dec 10.