A plant-derived compound may treat patients with diseases caused by Gα mutations.

Vertebrate jaw development is coordinated by highly conserved ligand-receptor systems such as the peptide ligand Endothelin 1 (Edn1) and receptor type A (Ednra), which are required for patterning of lower structures. The Edn1/Ednra signaling pathway establishes identity progenitor cells regulating expression numerous genes, but intracellular mechanisms linking activation to gene regulation remain poorly understood. As a first step towards elucidating this mechanism, we examined function...

Grapheme-color synesthesia is a heritable trait where graphemes ("2") elicit the concurrent perception of specific colors (red). Researchers have questioned whether synesthetic experiences are meaningful or simply arbitrary associations and these perceptual conceptual. To address fundamental questions, ERPs were recorded as 12 synesthetes read statements such "The Coca-Cola logo white 2," in which final grapheme induced color that was either contextually congruous (red) incongruous...

Auriculocondylar syndrome 2 (ARCND2) is a rare autosomal dominant craniofacial malformation linked to multiple genetic variants in the coding sequence of phospholipase C β4 (PLCB4). PLCB4 direct signaling effector endothelin receptor type A (EDNRA)-Gq/11 pathway, which establishes identity neural crest cells (NCCs) that form lower jaw and middle ear structures. However, functional consequences on EDNRA not known. Here, we show, using reporter assays, known resulting from missense mutations...

Neural crest cells (NCCs) within the mandibular and maxillary prominences of first pharyngeal arch are initially competent to respond signals from either region. However, mechanisms that only partially understood establish developmental tissue boundaries ensure spatially correct patterning. In 'hinge caps' model facial development, both ventral (the caps) pattern adjacent tissues whereas intervening region, referred as maxillomandibular junction hinge), maintains separation domains. One cap...

The R7 regulator of G protein signaling family (R7-RGS) critically regulates nervous system development and function. Mice lacking all R7-RGS subtypes exhibit diverse neurological phenotypes, humans bearing mutations in the retinal isoform RGS9-1 have vision deficits. Although each subtype forms heterotrimeric complexes with Gβ5 R7-RGS-binding (R7BP) that regulate protein-coupled receptor by accelerating deactivation Gi/o α-subunits, several phenotypes knock-out mice are not readily...

Abstract Craniofacial morphogenesis is regulated in part by signaling from the Endothelin receptor type A (EDNRA). Pathogenic variants EDNRA pathway components , GNAI3 PCLB4 and EDN1 cause Mandibulofacial Dysostosis with Alopecia (MFDA), Auriculocondylar syndrome (ARCND) 1, 2, 3, respectively. However, cardiovascular development normal MFDA ARCND individuals, unlike Ednra knockout mice. One explanation may be that partial remains ARCND, as mice reduced, but not absent, also lack a phenotype....

Regulator of G protein signaling 2 (RGS2) controls by receptors coupled to the Gq/11 class heterotrimeric proteins. RGS2 deficiency causes several phenotypes in mice and occurs diseases, including hypertension which a proteolytically unstable mutant has been reported. However, mechanisms functions proteolysis remain poorly understood. Here we addressed these questions identifying degradation signals RGS2, studying dynamic regulation Gq/11-evoked Ca2+ vascular contraction. We identified novel...

Abstract Vertebrate jaw development is coordinated by highly conserved ligand-receptor systems such as the peptide ligand Endothelin 1 (Edn1) and receptor type A (Ednra), which are required for patterning of lower structures. The Edn1/Ednra signaling pathway establishes identity progenitor cells regulating expression numerous genes, but intracellular mechanisms linking activation to gene regulation remain poorly understood. As a first step towards elucidating this mechanism, we examined...

Abstract Constitutively activating mutations in GNAQ (Gαq) or GNA11 (Gα11) are the oncogenic drivers of uveal (eye) melanoma (UM), occurring over 90% tumors. We show that constitutively active Gαq UM cells can be targeted by cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP exchange allosterically to trap inactive GDP-bound Gαβγ heterotrimers, and allosteric inhibition other Gα subunits achieved introduction an binding site. In driven Gαq, second messenger signaling, arrests...

Abstract Uveal (eye) melanoma is a highly aggressive cancer, in which almost half of patients develop distant metastases that are refractory to therapy. In particular, metastatic uveal has been clinically unresponsive the immunotherapeutic agents have shown success skin tumors, making need for novel therapeutic approaches all more urgent. Unlike melanomas, driven by BRAF and NRAS mutations, melanomas arise typically from mutations result constitutive activity alpha subunit heterotrimeric...

Abstract Constitutively active G protein α-subunits are oncogenic drivers of several cancers, most notably in uveal (eye) melanoma (UM), which have constitutively activating mutations GNAQ(Gαq) or GNA11(Gα11) over 90% tumors. Therapeutic intervention by targeted inhibition Gα subunits cancer has yet to be achieved. Here we show that Gαq UM cells can the cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP exchange allosterically trap inactive GDP-bound Gαβγ heterotrimers, and allosteric...

Abstract Constitutively activating mutations in the G-protein alpha subunits GNAQ(Gαq) and GNA11(Gα11) act as oncogenic drivers over 90% of uveal (eye) melanoma (UM) tumors. We show that constitutively active Gαq Gα11 can be targeted UM cells by cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP guanine nucleotide exchange allosterically to trap Gαq/11 inactive GDP-bound Gαβγ heterotrimers. second messenger signaling, arrests proliferation reinstates melanocytic differentiation driven or...

Constitutively activating mutations in the G-protein alpha subunits GNAQ(Gαq) and GNA11(Gα11) act as oncogenic drivers over 90% of uveal (eye) melanoma (UM) tumors. We show that constitutively active Gαq Gα11 can be targeted UM cells by cyclic depsipeptide FR900359 (FR). FR inhibits GDP/GTP guanine nucleotide exchange allosterically to trap Gαq/11 inactive GDP-bound Gαβγ heterotrimers. second messenger signaling, arrests proliferation reinstates melanocytic differentiation driven or Gα11. At...

Abstract Neural crest cells (NCCs) within the mandibular and maxillary portions of first pharyngeal arch are initially competent to respond signals from either region. However, mechanisms that only partially understood establish developmental tissue boundaries ensure spatially correct patterning. In Hinge Caps model facial development, both ventral prominences, referred as caps, pattern adjacent tissues while intervening region, known hinge, maintains separation domains. One cap signal is...