The role of A-kinase anchoring proteins in cancer development

Reggi, Erica; Diviani, Dario

doi:10.1016/j.cellsig.2017.09.011

Cited by 36 publications

(32 citation statements)

References 163 publications

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“…The AKAP-Lbc-mediated RhoA activation is associated with the development of cardiac hypertrophy [ 59 ] and cancer [ 60 ]. Therefore, the development of an inhibitor of the interaction has clinical implications.…”

Section: Discussionmentioning

confidence: 99%

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

et al. 2018

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Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.

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Section: Discussionmentioning

confidence: 99%

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

et al. 2018

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“…AKAP12 (also known as gravin, AKAP250, or SSeCKS) is expressed in various cell types of the cardiovascular system including vascular smooth muscle and endothelial cells, cardiomyocytes, and cardiac fibroblasts [159][160][161][162]. In addition of interacting with PKA, AKAP12 also associates with β-ARs, PKC, polo-line kinase 1, calmodulin, and PDE4D [163][164][165][166][167][168]. In mouse hearts, AKAP12 expression is strongly downregulated in response to chronic exposure to profibrotic agonists such as Ang-II [169].…”

Section: Akap12mentioning

confidence: 99%

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

Delaunay

Osman

Kaiser

et al. 2019

Cells

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Myocardial stress and injury invariably promote remodeling of the cardiac tissue, which is associated with cardiomyocyte death and development of fibrosis. The fibrotic process is initially triggered by the differentiation of resident cardiac fibroblasts into myofibroblasts. These activated fibroblasts display increased proliferative capacity and secrete large amounts of extracellular matrix. Uncontrolled myofibroblast activation can thus promote heart stiffness, cardiac dysfunction, arrhythmias, and progression to heart failure. Despite the well-established role of myofibroblasts in mediating cardiac disease, our current knowledge on how signaling pathways promoting fibrosis are regulated and coordinated in this cell type is largely incomplete. In this respect, cyclic adenosine monophosphate (cAMP) signaling acts as a major modulator of fibrotic responses activated in fibroblasts of injured or stressed hearts. In particular, accumulating evidence now suggests that upstream cAMP modulators including G protein-coupled receptors, adenylyl cyclases (ACs), and phosphodiesterases (PDEs); downstream cAMP effectors such as protein kinase A (PKA) and the guanine nucleotide exchange factor Epac; and cAMP signaling organizers such as A-kinase anchoring proteins (AKAPs) modulate a variety of fundamental cellular processes involved in myocardial fibrosis including myofibroblast differentiation, proliferation, collagen secretion, and invasiveness. The current review will discuss recent advances highlighting the role of cAMP and AKAP-mediated signaling in regulating pathophysiological responses controlling cardiac fibrosis.

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“…Spatial and temporal coordination of PKA signalling is achieved by association with scaffolding proteins (AKAPs), which constitute a family of about 20 molecules. Through a specialized domain, AKAPs anchor in different subcellular microdomains at targeting sites, thus assembling macromolecular complexes and recruiting a variety of signalling proteins, including other kinases, PDEs, phosphatases and small G proteins [19]. PKA becomes active in the presence of micromolar concentrations of cAMP, which upon binding to the regulatory subunits induces their dissociation from the catalytic domains.…”

Section: Physiologic Effectors Of Camp In Hepatocytesmentioning

confidence: 99%

Targeting Cyclic AMP Signalling in Hepatocellular Carcinoma

Massimi

Ragusa

Cardarelli

et al. 2019

Cells

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Hepatocellular carcinoma (HCC) is a major healthcare problem worldwide, representing one of the leading causes of cancer mortality. Since there are currently no predictive biomarkers for early stage diagnosis, HCC is detected only in advanced stages and most patients die within one year, as radical tumour resection is generally performed late during the disease. The development of alternative therapeutic approaches to HCC remains one of the most challenging areas of cancer. This review focuses on the relevance of cAMP signalling in the development of hepatocellular carcinoma and identifies the modulation of this second messenger as a new strategy for the control of tumour growth. In addition, because the cAMP pathway is controlled by phosphodiesterases (PDEs), targeting these enzymes using PDE inhibitors is becoming an attractive and promising tool for the control of HCC. Among them, based on current preclinical and clinical findings, PDE4-specific inhibitors remarkably demonstrate therapeutic potential in the management of cancer outcomes, especially as adjuvants to standard therapies. However, more preclinical studies are warranted to ascertain their efficacy during the different stages of hepatocyte transformation and in the treatment of established HCC.

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The role of A-kinase anchoring proteins in cancer development

Cited by 36 publications

References 163 publications

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

Targeting Cyclic AMP Signalling in Hepatocellular Carcinoma

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