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The adenosine 3′,5′-cyclic monophosphate–protein kinase A (cAMP-PKA) signaling pathway is highly utilized in human physiology. It is a crucial component of development and is vital to cellular function in nearly all tissues. Indeed, genetic mutations to cAMP-PKA machinery are found in many pathologies, including multiple cancers, cardiac myxoma, neurodevelopmental disorders, and hypercortisolism. Cyclic AMP and PKA were first identified as vital components in cortisol synthesis over 50 years ago, yet the cellular mechanisms connecting PKA to cortisol production are still not well understood. This article will review evidence for PKA’s roles in adrenal gland zona fasciculata steroidogenesis and consider recent studies of the stress hormone disease adrenal Cushing’s syndrome to synthesize a current model for cAMP-PKA actions in cortisol production.

Dendritic spines are the receptive contacts at most excitatory synapses in the central nervous system. Spines are dynamic in the developing brain, changing shape as they mature as well as appearing and disappearing as they make and break connections. Spines become much more stable in adulthood, and spine structure must be actively maintained to support established circuit function. At the same time, adult spines must retain some plasticity so their structure can be modified by activity and experience. As such, the regulation of spine stability and remodeling in the adult animal is critical for normal function, and disruption of these processes is associated with a variety of late onset diseases including schizophrenia and Alzheimer's disease. The extracellular matrix (ECM), composed of a meshwork of proteins and proteoglycans, is a critical regulator of spine and synapse stability and plasticity. While the role of ECM receptors in spine regulation has been extensively studied, considerably less research has focused directly on the role of specific ECM ligands. Here, we review the evidence for a role of several brain ECM ligands and remodeling proteases in the regulation of dendritic spine and synapse formation, plasticity, and stability in adults.

Cellular identity in metazoan organisms is frequently established through lineage-specifying transcription factors, which control their own expression through transcriptional positive feedback, while antagonizing the developmental networks of competing lineages. Here, we have uncovered a distinct positive feedback loop that arises from the reciprocal stabilization of the tyrosine kinase ABL and the transcriptional coactivator TAZ. Moreover, we determined that this loop is required for osteoblast differentiation and embryonic skeletal formation. ABL potentiated the assembly and activation of the RUNX2-TAZ master transcription factor complex that is required for osteoblastogenesis, while antagonizing PPARγ-mediated adipogenesis. ABL also enhanced TAZ nuclear localization and the formation of the TAZ-TEAD complex that is required for osteoblast expansion. Last, we have provided genetic data showing that regulation of the ABL-TAZ amplification loop lies downstream of the adaptor protein 3BP2, which is mutated in the craniofacial dysmorphia syndrome cherubism. Our study demonstrates an interplay between ABL and TAZ that controls the mesenchymal maturation program toward the osteoblast lineage and is mechanistically distinct from the established model of lineage-specific maturation.

A-kinase anchoring proteins (AKAPs) shape second-messenger signaling responses by constraining protein kinase A (PKA) at precise intracellular locations. A defining feature of AKAPs is a helical region that binds to regulatory subunits (RII) of PKA. Mining patient-derived databases has identified 42 nonsynonymous SNPs in the PKA-anchoring helices of five AKAPs. Solid-phase RII binding assays confirmed that 21 of these amino acid substitutions disrupt PKA anchoring. The most deleterious side-chain modifications are situated toward C-termini of AKAP helices. More extensive analysis was conducted on a valine-to-methionine variant in the PKA-anchoring helix of AKAP18. Molecular modeling indicates that additional density provided by methionine at position 282 in the AKAP18γ isoform deflects the pitch of the helical anchoring surface outward by 6.6°. Fluorescence polarization measurements show that this subtle topological change reduces RII-binding affinity 8.8-fold and impairs cAMP responsive potentiation of L-type Ca2+ currents in situ. Live-cell imaging of AKAP18γ V282M-GFP adducts led to the unexpected discovery that loss of PKA anchoring promotes nuclear accumulation of this polymorphic variant. Targeting proceeds via a mechanism whereby association with the PKA holoenzyme masks a polybasic nuclear localization signal on the anchoring protein. This led to the discovery of AKAP18ε: an exclusively nuclear isoform that lacks a PKA-anchoring helix. Enzyme-mediated proximity-proteomics reveal that compartment-selective variants of AKAP18 associate with distinct binding partners. Thus, naturally occurring PKA-anchoring-defective AKAP variants not only perturb dissemination of local second-messenger responses, but also may influence the intracellular distribution of certain AKAP18 isoforms.

Fibrolamellar carcinoma (FLC) is a rare liver cancer. FLCs uniquely produce DNAJ-PKAc, a chimeric enzyme consisting of a chaperonin-binding domain fused to the Cα subunit of protein kinase A. Biochemical analyses of clinical samples reveal that a unique property of this fusion enzyme is the ability to recruit heat shock protein 70 (Hsp70). This cellular chaperonin is frequently up-regulated in cancers. Gene-editing of mouse hepatocytes generated disease-relevant AML12DNAJ-PKAc cell lines. Further analyses indicate that the proto-oncogene A-kinase anchoring protein-Lbc is up-regulated in FLC and functions to cluster DNAJ-PKAc/Hsp70 sub-complexes with a RAF-MEK-ERK kinase module. Drug screening reveals Hsp70 and MEK inhibitor combinations that selectively block proliferation of AML12DNAJ-PKAc cells. Phosphoproteomic profiling demonstrates that DNAJ-PKAc biases the signaling landscape toward ERK activation and engages downstream kinase cascades. Thus, the oncogenic action of DNAJ-PKAc involves an acquired scaffolding function that permits recruitment of Hsp70 and mobilization of local ERK signaling. Fibrolamellar carcinoma (or FLC for short) is a rare type of liver cancer that affects teenagers and young adults. FLC tumors are often resistant to standard radiotherapy or chemotherapy treatments. The only way to treat FLC is to remove tumors by surgery. However, often the tumors come back after initial treatment and spread to other locations. Therefore, there is a genuine need to improve the treatment options available to FLC patients. The tumor cells of FLC patients contain a genetic defect that fuses together two genes, which produce proteins called DNAJ and PKAc. Normally, DNAJ helps other proteins in the cell to fold into their correct shapes, while PKAc is an enzyme that can control how cells communicate. However, it is not clear what the abnormal DNAJ-PKAc fusion protein does, or how it causes FLC. Turnham, Smith et al. have now used gene editing to make mouse liver cells that mimic the human FLC mutation. Biochemical experiments on these cells showed that the DNAJ-PKAc protein brings together unique combinations of enzymes that drive uncontrolled cell growth. Analyzing cells taken from tumors in FLC patients confirmed that these enzymes are also activated in the human disease. Turnham, Smith et al. also found that combinations of drugs that simultaneously target the DNAJ-PKAc protein and the recruited enzymes slowed down the growth of FLC cells. More experiments are now needed to test these drug combinations on human FLC cells or in mice.

Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

Insects have evolved a variety of neurohormones that enable them to maintain nutrient and osmotic homeostasis. Here, we characterized the ion transport peptide (ITP) signaling system in Drosophila . The Drosophila ITP gene can generate three different peptide isoforms: ITP amidated (ITPa) and two ITP-like (ITPL1 and ITPL2) isoforms. We comprehensively characterized the expression of all three ITP isoforms in the nervous system and peripheral tissues. Our analyses reveal widespread expression of ITP isoforms. Moreover, we show that ITPa-producing neurons are activated and release ITPa during dehydration. Furthermore, recombinant Drosophila ITPa inhibits diuretic peptide-induced renal tubule secretion ex vivo, thus confirming its role as an anti-diuretic hormone. Using a phylogenetic-driven approach, an ex vivo secretion assay and a heterologous mammalian cell-based assay, we identified and functionally characterized Gyc76C, a membrane guanylate cyclase, as a bona fide Drosophila ITPa receptor. Extensive anatomical mapping of Gyc76C reveals that it is highly expressed in larval and adult tissues associated with osmoregulation (renal tubules and rectum) and metabolic homeostasis (fat body). Consistent with this expression, knockdown of Gyc76C in renal tubules impacts tolerance to osmotic and ionic stresses, whereas knockdown specifically in the fat body impacts feeding, nutrient homeostasis, and associated behaviors. We also complement receptor knockdown experiments with ITP knockdown and ITPa overexpression in ITPa-producing neurons. Lastly, we utilized connectomics and single-cell transcriptomics to identify pathways via which ITP neurons integrate hygrosensory inputs and interact with other homeostatic hormonal pathways. Taken together, our systematic characterization of ITP signaling establishes a tractable system to decipher how a small set of neurons integrates diverse inputs to orchestrate systemic homeostasis in Drosophila .

In this paper, an exact expression for the average bit error probability was obtained for the λ-MRC detector, proposed in Sendonaris et al. (IEEE Trans Commun 51: 1927-1938, IEEE Trans. Commun 51: 1939-1948), under Rayleigh fading channel. In addition, a very accurate approximation was obtained to calculate the average bit error probability for any power allocation scheme. Our expressions allow to investigate the possible gains and situations where cooperation can be beneficial.

Insects have evolved a variety of neurohormones that enable them to maintain nutrient and osmotic homeostasis. Here, we characterized the ion transport peptide (ITP) signaling system in Drosophila . The Drosophila ITP gene can generate three different peptide isoforms: ITP amidated (ITPa) and two ITP-like (ITPL1 and ITPL2) isoforms. We comprehensively characterized the expression of all three ITP isoforms in the nervous system and peripheral tissues. Our analyses reveal widespread expression of ITP isoforms. Moreover, we show that ITPa-producing neurons are activated and release ITPa during dehydration. Furthermore, recombinant Drosophila ITPa inhibits diuretic peptide-induced renal tubule secretion ex vivo, thus confirming its role as an anti-diuretic hormone. Using a phylogenetic-driven approach, an ex vivo secretion assay and a heterologous mammalian cell-based assay, we identified and functionally characterized Gyc76C, a membrane guanylate cyclase, as a bona fide Drosophila ITPa receptor. Extensive anatomical mapping of Gyc76C reveals that it is highly expressed in larval and adult tissues associated with osmoregulation (renal tubules and rectum) and metabolic homeostasis (fat body). Consistent with this expression, knockdown of Gyc76C in renal tubules impacts tolerance to osmotic and ionic stresses, whereas knockdown specifically in the fat body impacts feeding, nutrient homeostasis, and associated behaviors. We also complement receptor knockdown experiments with ITP knockdown and ITPa overexpression in ITPa-producing neurons. Lastly, we utilized connectomics and single-cell transcriptomics to identify pathways via which ITP neurons integrate hygrosensory inputs and interact with other homeostatic hormonal pathways. Taken together, our systematic characterization of ITP signaling establishes a tractable system to decipher how a small set of neurons integrates diverse inputs to orchestrate systemic homeostasis in Drosophila .

In this paper, an exact expression for the average bit error probability was obtained for the [lamda]-MRC detector, proposed in Sendonaris et al. (IEEE Trans Commun 51: 1927-1938, IEEE Trans. Commun 51: 1939-1948), under Rayleigh fading channel. In addition, a very accurate approximation was obtained to calculate the average bit error probability for any power allocation scheme. Our expressions allow to investigate the possible gains and situations where cooperation can be beneficial.[PUBLICATION ABSTRACT]