Comparative
            <i>PRKAR1A</i>
            genotype–phenotype analyses in humans with Carney complex and
            <i>prkar1a</i>
            haploinsufficient mice

Veugelers, Mark; Wilkes, David; Burton, Kimberly A.; McDermott, Deborah A.; Song, Yee Jiun; Goldstein, Martin; Perle, Krista La; Vaughan, Carl J.; O'Hagan, Art; Bennett, Kenneth R.; Meyer, Beat J.; Legius, Eric; Karttunen, Mervi; Norio, Reijo; Kääriäinen, Helena; Lavyne, Michael H.; Neau, Jean Philippe; G, Richter; Kırali, Kaan; Farnsworth, Alan; Stapleton, Karen; Morelli, P.; Takanashi, Yoshinori; Bamforth, John Steven; Eitelberger, Franz; Noszian, Irene; Manfroi, Waldimiro; Powers, James C.; Mochizuki, Yoshinari; Imai, Tsuneo; Ko, G. T. C.; Driscoll, Deborah A.; Goldmuntz, Elizabeth; Edelberg, Jay M.; Collins, Amanda; Eccles, Diana; Irvine, Alan D.; McKnight, G. Stanley; Basson, Craig T.

doi:10.1073/pnas.0405535101

Cited by 144 publications

(126 citation statements)

References 39 publications

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“…Others have reported that cAMP inhibits the mammalian target of rapamycin complex-1 and -2 activation via a PKAdependent mechanism 46 . In a mouse model of inherited tumour syndrome Carney complex (CNC) with defect in the regulatory subunit 1a of PKA, there is evidence that prkar1a þ / À (regulatory subunit 1a of PKA) mice developed HCC, while the PKA activity in these mice remained unchanged 47 . However, in another study, CNC patients with prkar1a mutations have been shown to develop a spectrum of carcinomas but not HCC 48 .…”

Section: Discussionmentioning

confidence: 99%

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Chan

Sze

et al. 2013

Nat Commun

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Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that encodes a RhoGTPase-activating protein (RhoGAP) and is frequently inactivated in many human cancers. The RhoGAP activity of DLC1 against Rho signalling is well documented and is strongly associated with the tumour suppressor functions of DLC1. However, the mechanism by which the RhoGAP activity of DLC1 is regulated remains obscure. Here, we report that phosphorylation of DLC1 at Ser549 by cyclic AMP-dependent protein kinase A contributes to enhanced RhoGAP activity and promotes the activation of DLC1, which suppresses hepatoma cell growth, motility and metastasis in both in vitro and in vivo models. Intriguingly, we found that Ser549 phosphorylation induces the dimerization of DLC1 and that inducible dimerization of DLC1 can rescue the tumour suppressive and RhoGAP activities of DLC1 containing a Ser549 deletion. Our study establishes a novel regulatory mechanism for DLC1 RhoGAP activity via dimerization induced by protein kinase A signalling.

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Section: Discussionmentioning

confidence: 99%

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

Chan

Sze

et al. 2013

Nat Commun

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“…Although PKAc activity is elevated in this condition, its role in the increased tumorigenesis in CNC has been questioned (21). Nevertheless, a recent study has suggested that elevated PKAc activity in the adrenal tissue of CNC patients, via activation of B-Raf, may augment the activity of MEK and Erk1/2 (44).…”

Section: Pp2a Exists In a Complex With Rsk1⅐pka⅐d-akap1 And Ht31mentioning

confidence: 99%

“…CNC is an autosomal dominant multiple neoplasia syndrome in which myxomas of the skin, heart, and/or vicera are recurrent and also associated with high incidence of endocrine and ovarian tumors as well as Schwannomas (18 -20). The majority of patients with the multiple neoplasia CNC syndrome harbor mutations in the PKAR1A gene (21) that result in PKARI␣ haploinsufficiency. Importantly, however, loss of heterozygosity or alterations in PKA activity may not contribute toward the tumorigenicity in either CNC patients or mouse model of CNC (21).…”

mentioning

confidence: 99%

“…The majority of patients with the multiple neoplasia CNC syndrome harbor mutations in the PKAR1A gene (21) that result in PKARI␣ haploinsufficiency. Importantly, however, loss of heterozygosity or alterations in PKA activity may not contribute toward the tumorigenicity in either CNC patients or mouse model of CNC (21). This suggests that loss of function(s) of PKARI␣ other than inhibition of PKA activity is(are) involved in the enhanced tumorigenicity in CNC patients and in the murine CNC model.…”

mentioning

confidence: 99%

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The PKARIα Subunit of Protein Kinase A Modulates the Activation of p90RSK1 and Its Function

Chaturvedi

Cohen

Taunton

et al. 2009

Journal of Biological Chemistry

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Cyclic AMP-dependent protein kinase (PKA) 3 plays a pivotal role in manifesting an array of biological actions ranging from cell proliferation and tumorigenesis to increased inotropic and chronotropic effects in the heart as well as regulation of long term potentiation and memory. The PKA holoenzyme is a heterotetramer and consists of two catalytic (PKAc) subunits bound to a dimer of regulatory subunits. To date, four isoforms of the PKAc (PKAc␣, PKAc␤, PKAc␥, and PKAc␦) and four isoforms of the regulatory subunits (RI␣, RI␤, RII␣, and RII␤) have been described (1). The various isoforms of PKA subunits are expressed differently in a tissue-and cell-specific manner (2). In addition to binding and inhibiting the activity of PKAc via their pseudo substrate region (3-6), the R subunits also interact with PKA-anchoring proteins (AKAPs) and facilitate the localization of PKA in specific subcellular compartments (7,8). More than 50 AKAP family members have been described, and although most of these have a higher affinity for the RII subunits (9), certain AKAPs such as D-AKAP1 and D-AKAP2 preferentially bind the PKARI␣ subunit (10 -12). Because the AKAPs also bind other signaling molecules such as phosphatases (PP2B) and kinases (protein kinase C), they act as scaffolds to organize and integrate specific signaling events within specific compartments in the cells (7,8,13,14).We have shown that the PKARI␣ and PKAc␣ subunits of PKA interact with the inactive and active forms of p90 RSK1 (RSK1), respectively (15). Binding of inactive RSK1 to PKARI␣ decreases the interactions between PKARI␣ and PKAc, whereas the association of active RSK1 with PKAc increases interactions between PKARI␣ and PKAc such that larger amounts of cAMP are required to activate PKAc in the presence of active RSK1 (15). Moreover, the indirect (via subunits of PKA) interaction of RSK1 with AKAPs is required for the nuclear localization of active RSK1 (15), and disruption of the interactions of RSK1⅐PKA complex from AKAPs results in increased cytoplasmic distribution of active RSK1 with a concomitant increase in phosphorylation of its cytosolic substrates such as BAD and reduced cellular apoptosis (15). These findings show the functional and biological significance of RSK1⅐ PKA⅐AKAP interactions.Besides inhibiting PKAc activity, the physiological role of PKARI␣ is underscored by the findings that mutations in the PKAR1A gene that result in haploinsufficiency of PKARI␣ are

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“…This gene maps to 17q22-24, a locus that has been implicated, by linkage analysis, in a dominantly multiple neoplasia inherited syndrome with many clinical and pathological manifestations, the Carney complex (CNC) (46,47). Heterozygous inactivating germline mutations of PRKAR1A have been demonstrated in about 45 -65% of CNC families (47,48). LOH at 17q22-24 is observed in tumours from CNC patients, suggesting that PRKAR1A is a tumour-suppressor gene.…”

Section: Prkar1a Gene and Locus 17q22-24mentioning

confidence: 99%

Molecular genetics of adrenocortical tumours, from familial to sporadic diseases

2005

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Adrenal masses can be detected in up to 4% of the population, and are mostly of adrenocortical origin. Adrenocortical tumours (ACTs) may be responsible for excess steroid production and, in the case of adrenocortical cancers, for morbidity or mortality due to tumour growth. Our understanding of the pathogenesis of ACTs is more limited than that for other tumours. However, studies of the genetics of ACTs have led to major advances in this field in the last decade. The identification of germline molecular defects in the hereditary syndrome responsible for ACTs has facilitated progress. Indeed, similar molecular defects have since been identified as somatic alterations in sporadic tumours. The familial diseases concerned are Li-Fraumeni syndrome, which may be due to germline mutation of the tumour-suppressor gene TP53 and Beckwith -Wiedemann syndrome, which is caused by dysregulation of the imprinted IGF-II locus at 11p15. ACTs also occur in type 1 multiple endocrine neoplasia (MEN 1), which is characterized by a germline mutation of the menin gene. Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) has been observed in Carney complex patients presenting inactivating germline PRKAR1A mutations. Interestingly, allelic losses at 17p13 and 11p15 have been demonstrated in sporadic adrenocortical cancer and somatic PRKAR1A mutations have been found in secreting adrenocortical adenomas. More rarely, mutations in Gs protein (gsp) and the gene for ACTH receptor have been observed in ACTs. The genetics of another group of adrenal diseases that can lead to adrenal nodular hyperplasia -congenital adrenal hyperplasia (CAH) and glucocorticoid-remediable aldosteronism (GRA) -have also been studied extensively. This review summarizes recent advances in the genetics of ACTs, highlighting both improvements in our understanding of the pathophysiology and the diagnosis of these tumours.

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Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice

Cited by 144 publications

References 39 publications

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis

The PKARIα Subunit of Protein Kinase A Modulates the Activation of p90RSK1 and Its Function

Molecular genetics of adrenocortical tumours, from familial to sporadic diseases

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