Biology subjects

Taylor, S. S.

Publications and source records attributed to Taylor, S. S..

At least 19 recordsLinked to original sources

bioRxiv2026

Selective knockout of PKA regulatory subunits reveal opposite catalytic and metabolic consequences with implications for Alzheimer's disease

cAMP-dependent Protein Kinase A (PKA) is a master regulator of cell signaling involved in energy metabolism, synaptic plasticity, and stress response. Dysregulated PKA signaling is implicated in diseases including neurodegeneration and cancer. PKA catalytic activity is regulated by two nonredundant regulatory subunits, Type I (RI/RI{beta}) and Type II (RII/RII{beta}), whose divergent functions are not fully understood. We generated double-knockout (KO) cell lines of RI/RI{beta} and RII/RII{beta} subunits and performed multiplexed MS-based proteomic and phosphoproteomic profiling under basal and glucose-perturbed conditions. We found that RI and RII loss drives distinct, and often opposite, remodeling of the cellular proteome and phosphoproteome. While both mutants blunted metabolic flexibility to glycolytic stressors and stimuli, RI and RII KO cells exhibited elevated and depressed glycolytic signaling, respectively. Interestingly, RI KO increased the abundance and kinase activity of the PKA catalytic subunit C isoform, leading to an increase in PKA substrate phosphorylation, whereas RII KO decreased the abundance, kinase activity, and substrate phosphorylation by the catalytic subunit C{beta} isoform. Notably, one of the most differentially affected PKA sites between RI and RII KOs maps to Tau, whose hyperphosphorylation is a hallmark of Alzheimers disease. Loss of RI increased Tau phosphorylation, which was not only caused by increased PKA catalytic activity, but also a higher binding affinity of Tau to RII subunits on the negatively-charged flexible linker region. Overall, the present study demonstrates that PKA RI and RII subunits play nonredundant roles in modulating PKA activity, metabolic flexibility, and phospho-regulation of key disease-associated substrates such as Tau.

biochemistry↗

bioRxiv2026

S-nitrosylation of protein kinase A is required for its activation by GPCRs

Stimulation of many G protein-coupled receptors (GPCRs) increases cyclic adenosine monophosphate (cAMP) and nitric oxide (NO). While cAMP-dependent activation of protein kinase A (PKA) is a central regulatory mechanism, a parallel role for NO in GPCR transduction has not been established. Here we show that upon stimulation of multiple GPCRs in heart, brain, and fat, the regulatory subunits of PKA undergo enzymatic S-nitrosylation by SNO-CoA-assisted nitrosylase (SCAN). S-nitrosylation by SCAN is required for dissociation of PKA holoenzymes and activation of PKA. In transgenic and cardiovascular disease models, impaired adrenergic stimulation is identified with deficient S-nitrosylation of PKA, which can be rescued by the drug sodium nitroprusside. Our work suggests a new understanding of GPCR physiology with direct application to the clinical setting.

physiology↗

bioRxiv2025

A clinical-stage oncology compound selectively targets drug-resistant cancers

Re-evaluating existing clinical compounds can uncover previously unrecognized mechanisms that reshape a drugs therapeutic potential. The small molecule Procaspase-Activating Compound 1 (PAC-1) entered oncology testing as a proposed activator of caspase-driven apoptosis. Here, we show that PAC-1-driven cytotoxicity occurs in the absence of executioner caspase expression, demonstrating that its anti-cancer activity occurs via an alternative mechanism. We provide genetic, biochemical, and biophysical evidence demonstrating that PAC-1 functions as a highly selective iron chelator that eliminates cancer cells by disrupting iron homeostasis. Unexpectedly, we discovered that expression of the key chemotherapy-resistance pump MDR1 confers marked hypersensitivity to PAC-1 treatment. While PAC-1 is only weakly effluxed by MDR1 under basal conditions, this process is potentiated when PAC-1 is bound to iron. Consequently, PAC-1 induces progressive iron depletion and selective cytotoxicity in otherwise drug-resistant MDR1-expressing cancer cells. Together, these findings redefine PAC-1s mechanism-of-action and establish a framework for exploiting multidrug resistance as a therapeutic vulnerability through targeted iron starvation.

cancer biology↗

bioRxiv2025

Transcriptional Circuitry in HGSOC: A Dynamic Three-State Model Informed by a Living Biobank of Purified Tumour Fractions

High-grade serous ovarian cancer (HGSOC) is a heterogeneous disease, but efforts to define transcriptional subtypes using bulk RNA sequencing have been confounded by the presence of non-malignant cells. As a result, it remains unclear whether tumour-cell-intrinsic states exist, and whether these represent stable disease subtypes or are dynamically remodelled during disease progression and treatment. Here, we address this question using a living biobank of patient-derived ovarian cancer models (OCMs) cultured as purified tumour-cell populations under uniform conditions. RNA sequencing followed by unsupervised non-negative matrix factorisation (NMF) revealed a robust, hierarchical architecture comprising three core tumour-cell-intrinsic subtypes: the Alpha cluster, marked by cell-cycle deregulation and E2F-driven replication stress; the Beta cluster, defined by tumour-cell-intrinsic immune mimicry and inflammatory signalling; and the Gamma cluster, characterised by epithelial identity, extracellular matrix engagement, and metabolic adaptation. At higher clustering resolution, a fourth cluster, Delta, emerged as a Gamma sub-lineage distinguished by a vesicle-oriented, neuronal-like secretory programme. By projecting cluster labels onto a subset of matched longitudinal OCMs using non-negative least squares, we show that while some tumours retain stable subtype identities, others display transcriptional plasticity, including transitions from epithelial-like Gamma states to more proliferative or secretory phenotypes. Together, these findings define the core architecture and dynamic potential of tumour-cell-intrinsic transcriptional states within HGSOC, thereby bridging legacy bulk classifications with emerging single-cell insights, establishing a framework for more precise patient stratification.

cancer biology↗

bioRxiv2025

Exploring CDK4/6-Dependencies in ex vivo Ovarian Cancer Models

Ovarian cancer (OC) is a clinically and molecularly heterogeneous disease with limited treatment options for the majority of patients, particularly those with homologous-recombination-proficient high-grade serous ovarian cancer (HGSOC) and rarer subtypes such as low-grade serous ovarian cancer. Deregulation of the G1/S cell cycle network is common across all subtypes, suggesting subtype-agnostic vulnerabilities. Here, we assessed CDK4/6 dependency using the selective inhibitor palbociclib across 20 patient-derived ex vivo OC models. A subset of models, including four HGSOC and six rarer subtypes, exhibited marked sensitivity to palbociclib, characterised by low CDKN2A/CDKN2B expression, Rb hypophosphorylation, and G1 cell cycle arrest. In contrast, resistant models showed high CDKN2A expression and reduced or absent RB1. Notably, ABCB1 overexpression--a known resistance mechanism in OC--did not mediate palbociclib resistance. Analysis of longitudinal models revealed diminished CDK4/6 dependency following treatment, accompanied by increased CDKN2A expression. These findings support a model of G1/S control in which tumours diverge into CDK4/6- or CDK2-driven proliferation states, with CDKN2A as a potential biomarker to guide patient selection. The predominance of CDK4/6-inhibitor-resistant HGSOC highlights a priority population for CDK2-targeted therapies, offering new treatment strategies for patients with otherwise limited options.

cancer biology↗

bioRxiv2025

Transcriptome-Driven Constraint-Based Modelling Reveals Metabolic Targets for Ovarian Cancer

Constraint-based modelling (CBM) is a powerful computational approach that reconstructs cellular metabolism by integrating omics data with genome-scale metabolic models (GEMs), enabling in silico hypothesis generation and genetic engineering studies. Advances in high-throughput omics technologies and the complete mapping of the human genome have expanded the application of CBM to human systems. Given that altered metabolism is a hallmark of cancer, this disease represents an ideal context for developing and applying CBM workflows. Despite the presence of well-characterised metabolic signatures and vulnerabilities in ovarian cancer, this tumour type remains under-explored within the CBM field. Meanwhile, the limited efficacy of current therapies and the frequent emergence of chemoresistance underscore the need for novel, mechanism-based approaches to therapeutic discovery. In this study, we constructed ovarian cancer-specific metabolic models using an omics integration algorithm that incorporates transcriptomic data in a way that is directed by experimental growth measurements. Simulations identified multiple candidate molecules predicted to influence cancer cell proliferation. Among these, triosephosphate isomerase 1 (TPI1) was selected for experimental validation based on qualitative prioritisation criteria. Notably, model predictions were supported by RNA sequencing and proliferation assays, implicating TPI1 in ovarian cancer cell growth. Our results provide novel insights into the metabolic dependencies of ovarian cancer and demonstrate a multi-omics CBM workflow that may be broadly applicable for uncovering therapeutic vulnerabilities in other malignancies.

cancer biology↗

bioRxiv2025

Sex specific disruptions in Protein Kinase Cγ signaling in a mouse model of Spinocerebellar Ataxia Type 14

Spinocerebellar Ataxia Type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in the gene encoding protein kinase C gamma (PKC{gamma}), a Ca2+/diacylglycerol (DG)-dependent serine/threonine kinase dominantly expressed in cerebellar Purkinje cells. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in deficits in the cerebellum that are not observed upon simple deletion of the gene, and severe ataxia. To better understand the phenotypic impact of aberrant PKC{gamma} signaling in disease pathology, we developed a knock-in murine model of the SCA14 mutation {Delta}F48 in PKC{gamma}. This fully penetrant mutation is severe in humans and is mechanistically informative as it has high basal activity but is unresponsive to agonist stimulation. Genetic, behavioral, and molecular testing revealed that {Delta}F48 PKC{gamma} SCA14 mice have ataxia related phenotypes and an altered cerebellar phosphoproteome, effects that are more severe in male mice. Analysis of existing human data reveal that SCA14 has a significantly earlier age of onset for males compared with females. Our data from this clinically relevant mutation suggest that enhanced basal activity of PKC{gamma} is necessary and sufficient to cause ataxia and that treatment strategies to modulate aberrant PKC{gamma} may be particularly beneficial in males. SummaryNew mouse model of Spinocerebellar Ataxia Type 14 containing a clinically relevant mutation in PKC{gamma} identified underlying drivers of the disease and neuroprotection in females.

neuroscience↗

bioRxiv2024

A Structural Mechanism for Noncanonical GPCRSignal Transduction in the Hedgehog Pathway

SUMMARY PARAGRAPHThe Hedgehog (Hh) signaling pathway is fundamental to embryogenesis, tissue homeostasis, and cancer. Hh signals are transduced via an unusual mechanism: upon agonist-induced phosphorylation, the noncanonical G protein-coupled receptor SMOOTHENED (SMO) binds the catalytic subunit of protein kinase A (PKA-C) and physically blocks its enzymatic activity. By combining computational structural approaches with biochemical and functional studies, we show that SMO mimics strategies prevalent in canonical GPCR and PKA signaling complexes, despite little sequence or secondary structural homology. An intrinsically disordered region of SMO binds the PKA-C active site, resembling the PKA regulatory subunit (PKA-R) / PKA-C holoenzyme, while the SMO transmembrane domain binds a conserved PKA-C interaction hub, similar to other GPCR-effector complexes. In contrast with prevailing GPCR signal transduction models, phosphorylation of SMO promotes intramolecular electrostatic interactions that stabilize key structural elements within the SMO cytoplasmic domain, thereby remodeling it into a PKA-inhibiting conformation. Our work provides a structural mechanism for a central step in the Hh cascade and defines a paradigm for disordered GPCR domains to transmit signals intracellularly.

biochemistry↗

bioRxiv2023

Molecular Determinants and Signaling Effects of PKA RIα Phase Separation

Spatiotemporal regulation of intracellular signaling molecules, such as the 3,5-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures the specific execution of various cellular functions. Liquid-liquid phase separation (LLPS) of the ubiquitously expressed PKA regulatory subunit RI was recently identified as a major driver of cAMP compartmentation and signaling specificity. However, the molecular determinants of RI LLPS remain unclear. Here, we reveal that two separate dimerization interfaces combined with the cAMP-induced release of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence are required to drive RI condensate formation in cytosol, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RI pseudosubstrate region is critically involved in the formation of a non-canonical R:C complex, which serves to maintain low basal PKA activity in the cytosol by enabling the recruitment of active PKA-C to RI condensates. Our results suggest that RI LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.

cell biology↗

bioRxiv2023

The αC-β4 loop controls the allosteric cooperativity between nucleotide and substrate in the catalytic subunit of protein kinase A

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic subunit of protein kinase A (PKA). Not only this long-range synergistic action is involved in substrate recognition and fidelity, but it is also likely to regulate PKA association with regulatory subunits and other binding partners. To date, a complete understanding of the molecular determinants for this intramolecular mechanism is still lacking. Here, we integrated NMR-restrained molecular dynamics simulations and a Markov State Model to characterize the free energy landscape and conformational transitions of the catalytic subunit of protein kinase A (PKA-C). We found that the apoenzyme populates a broad free energy basin featuring a conformational ensemble of the active state of PKA-C (ground state) and other basins with lower populations (excited states). The first excited state corresponds to a previously characterized inactive state of PKA-C with the C helix swinging outward. The second excited state displays a disrupted hydrophobic packing around the regulatory (R) spine, with a flipped configuration of the F100 and F102 residues at the C-{beta}4 loop. To experimentally validate the second excited state, we mutated F100 into alanine (F100A) and used NMR spectroscopy to characterize the structural response of the kinase to ATP and substrate binding. While the catalytic efficiency of PKA-CF100A with a canonical peptide substrate remains unaltered, this mutation rearranges the C-{beta}4 loop conformation, interrupting the structural coupling of the two lobes and abolishing the allosteric binding cooperativity of the enzyme. The highly conserved C-{beta}4 loop emerges as a pivotal element able to control the synergistic binding between nucleotide and substrate. These results may explain how mutations or insertions near or within this motif affect the function and drug sensitivity in other homologous kinases.

biophysics↗

bioRxiv2023

Protein Kinase Structure and Dynamics: Role of the αC-β4 Loop

Although the C-{beta}4 loop is a stable feature of all protein kinases, the importance of this motif as a conserved element of secondary structure, as well as its links to the hydrophobic architecture of the kinase core, has been underappreciated. We first review the motif and then describe how it is linked to the hydrophobic spine architecture of the kinase core, which we first discovered using a computational tool, Local Spatial Pattern (LSP) alignment. Based on NMR predictions that a mutation in this motif abolishes the synergistic high-affinity binding of ATP and a pseudo substrate inhibitor, we used LSP to interrogate the F100A mutant. This comparison highlights the importance of the C-{beta}4 loop and key residues at the interface between the N- and C-lobes. In addition, we delved more deeply into the structure of the apo C-subunit, which lacks ATP. While apo C-subunit showed no significant changes in backbone dynamics of the C-{beta}4 loop, we found significant differences in the side chain dynamics of K105. The LSP analysis suggests disruption of communication between the N- and C-lobes in the F100A mutant, which would be consistent with the structural changes predicted by the NMR spectroscopy.

molecular biology↗

bioRxiv2023

Single-residue mutation in protein kinase C toggles between cancer and neurodegeneration

Conventional protein kinase C (PKC) isozymes tune the signaling output of cells, with loss-of-function somatic mutations associated with cancer and gain-of-function germline mutations identified in neurodegeneration. PKC with impaired autoinhibition is removed from the cell by quality-control mechanisms to prevent accumulation of aberrantly active enzyme. Here, we examine how a single residue in the C1A domain of PKC{beta}, arginine 42 (R42), permits quality-control degradation when mutated to histidine in cancer (R42H) and blocks downregulation when mutated to proline in the neurodegenerative disease spinocerebellar ataxia (R42P). Using FRET-based biosensors, we determined that mutation of R42 to any residue, including lysine, resulted in reduced autoinhibition as indicated by higher basal activity and faster agonist-induced plasma membrane translocation. R42 is predicted to form a stabilizing salt bridge with E655 in the C-tail and mutation of E655, but not neighboring E657, also reduced autoinhibition. Western blot analysis revealed that whereas R42H had reduced stability, the R42P mutant was stable and insensitive to activator-induced ubiquitination and downregulation, an effect previously observed by deletion of the entire C1A domain. Molecular dynamics (MD) simulations and analysis of stable regions of the domain using local spatial pattern (LSP) alignment suggested that P42 interacts with Q66 to impair mobility and conformation of one of the ligand-binding loops. Additional mutation of Q66 to the smaller asparagine (R42P/Q66N), to remove conformational constraints, restored degradation sensitivity to that of WT. Our results unveil how disease-associated mutations of the same residue in the C1A domain can toggle between gain- or loss-of-function of PKC.

molecular biology↗

bioRxiv2022

Capturing differences in the regulation of LRRK2 dynamics and conformational states by small molecule kinase inhibitors

Mutations in the human leucine rich repeat protein kinase-2 (LRRK2) create risk factors for Parkinsons Disease, and pathological functions of LRRK2 are often correlated with aberrant kinase activity. Past research has focused on developing selective LRRK2 kinase inhibitors. We showed previously that in addition to influencing intrinsic kinase activity, the global conformation of the LRRK2 protein plays a vital role in regulating LRRK2 signaling pathways. Deciphering the allosteric regulation in LRRK2 provides novel strategies for drug discovery. In this study, we combined enhanced sampling simulations with HDX-MS to analyze the inhibitor-induced dynamic changes and the allosteric communications in the C-terminal half of LRRK2, LRRK2RCKW. We find that a type I inhibitor (MLi-2) locks the kinase into a closed, active-like configuration, whereas a type II inhibitor (Rebastinib) shifts the kinase to an open, inactive configuration. While both type I and type II inhibitors reduce the kinase activity effectively, they have distinct effects on the LRRK2 conformational dynamics. Specifically, binding of MLi-2 stabilizes the kinase domain in a closed conformation and reduces the global dynamics of LRRK2RCKW, leading to a more compact LRRK2RCKW structure. In contrast, binding of Rebastinib stabilizes an open conformation where communication between the N- and C-lobe is severed, which promotes a more extended LRRK2RCKW structure. Rebastinib, based on HDX-MS, creates a more dynamic kinase domain especially at domain interfaces associated with the C-lobe. Our results also reveal the importance of the Dk-helix, which plays a crucial role in propagating communication between the kinase domain and the GTPase domain.

biochemistry↗

bioRxiv2022

Comparing multiscale, presence-only habitat suitability models created with structured survey data and community science data for a rare warbler species at the southern range margin

Golden-winged Warblers (Vermivora chrysoptera, Parulidae) are declining migrant songbirds that breed in the Great Lakes and Appalachian regions of North America. Within their breeding range, Golden-winged Warblers are found in early successional habitats adjacent to mature hardwood forest, and previous work has found that Golden-winged Warbler habitat preferences are scale-dependent. Golden-winged Warbler Working Group management recommendations were written to apply to large regions of the breeding range, but there may be localized differences in both habitat availability and preferences. Rapid declines at the southernmost extent of their breeding range in Western North Carolina and Georgia necessitate investigation into landscape characteristics governing distribution in this subregion. We describe patterns of Golden-winged Warbler presence in Western North Carolina by examining habitat variables at multiple spatial scales using data from standardized Audubon North Carolina (NC) surveys and unstructured community scientist checklists submitted to eBird. We compared model performance and predictions between Audubon NC and eBird models and found that Golden-winged Warbler presence is associated with sites which, at a local scale (150m), have more young forest, less mature forest, and more road cover, and at a landscape scale (2.5km), have less road cover. eBird and Audubon models had similar parameter estimates for all of the land cover variables and similar overall performance. Based on parameter estimates, road density at the landscape scale (2.5km) is the primary variable driving the difference between Golden-winged Warbler breeding sites and random background sites in Western North Carolina. Our results show that eBird data can produce species distribution modeling results that are similar to results obtained from more standardized survey methods.

ecology↗

bioRxiv2022

Molecular-Dynamics Simulation Methods for Macromolecular Crystallography

To assess the potential benefits of molecular-dynamics (MD) simulations for macromolecular crystallography (MX), we performed room-temperature X-ray diffraction studies of the catalytic subunit of mouse protein kinase A (PKA-C). We then performed crystalline MD simulations of PKA-C, computed simulated electron densities from the water, protein, and ion components of the MD simulations, and carefully compared them to the initial crystal structure. The results led to the development of an MD-MX analysis procedure and several associated methods: 1) density comparison to evaluate consistency between the MD and the initial crystal structure model; 2) water building to generate alternative solvent models; and 3) protein remodeling to improve the crystal structure where interpretation of density is unclear. This procedure produced a revised structure of PKA with a new ordered water model and a modified protein structure. The revisions yield new insights into PKA mechanisms, including: a sensitivity of the His294 conformation to protonation state, with potential consequences for regulation of substrate binding; a remodeling of the Lys217 side chain along with a bound phosphate; an alternative conformation for Lys213 associated with binding to the regulatory subunit; and an alternative conformation for catalytic base Asp166 and nearby waters, suggesting a mechanism of progression of the phosphotransfer reaction via changes in Mg2+ coordination. Based on the benefits seen applying these methods to PKA, we recommend incorporating our MD-MX procedure into MX studies, to decide among ambiguous interpretations of electron density that occur, inevitably, as part of standard model refinement.

biophysics↗

bioRxiv2021

Integrated Regulation of PKA by Fast and Slow Neurotransmission in the Nucleus Accumbens Controls Plasticity and Stress Responses

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RII{beta}. We find that glutamate-dependent reduction in Cdk5-dependent RII{beta} phosphorylation alters the PKA holoenzyme auto-inhibitory state to increase PKA signaling in response to dopamine. Disruption of RII{beta} phosphorylation by Cdk5, consequently, enhances cortico-ventral striatal synaptic plasticity. Acute and chronic stress in rats inversely modulate RII{beta} phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RII{beta} regulation by Cdk5 improves behavioral response to stress. This new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is likely important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.

neuroscience↗

bioRxiv2021

Two helices control the dynamic crosstalk between the catalytic domains of LRRK2

The two major molecular switches in biology, kinases and GTPases, are both contained in the Parkinsons Disease-related Leucine-rich repeat kinase 2 (LRRK2). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and Molecular Dynamics (MD) simulations, we generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 (LRRK2RCKW). We identified two helices that shield the kinase domain and regulate LRRK2 conformation and function. One docking helix in COR-B (Dk-Helix) tethers the COR-B domain to the C helix of the kinase domain and faces its Activation Loop, while the C-terminal helix (Ct-Helix) extends from the WD40 domain and interacts with both kinase lobes. The Ct-Helix and the N-terminus of the Dk-Helix create a "cap" that regulates the N-Lobe of the kinase domain. Our analyses reveal allosteric sites for pharmacological intervention and confirm the kinase domain as the central hub for conformational control.

biochemistry↗

bioRxiv2021

A PKA Inhibitor Motif within Smoothened Controls Hedgehog Signal Transduction

The Hedgehog (Hh) cascade is central to development, tissue homeostasis, and cancer. A pivotal step in Hh signal transduction is the activation of GLI transcription factors by the atypical G protein-coupled receptor (GPCR) Smoothened (SMO). How SMO activates GLI has remained unclear for decades. Here we show that SMO employs a decoy substrate sequence to physically block the active site of the PKA catalytic subunit (PKA-C) and extinguish its enzymatic activity. As a result, GLI is released from phosphorylation-induced inhibition. Using a combination of in vitro, cellular, and organismal models, we demonstrate that interfering with SMO / PKA pseudosubstrate interactions prevents Hh signal transduction. The mechanism we uncovered echoes one utilized by the Wnt cascade, revealing an unexpected similarity in how these two essential developmental and cancer pathways signal intracellularly. More broadly, our findings define a new mode of GPCR-PKA communication that may be harnessed by a range of membrane receptors and kinases.

biochemistry↗