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Nedd9 Restrains Renal Cystogenesis in Pkd1 Mice

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Nedd9 Restrains Renal Cystogenesis in Pkd1 Mice −/− Nedd9 restrains renal cystogenesis in Pkd1 mice Anna S. Nikonovaa, Olga V. Plotnikovaa,1, Victoria Serzhanovaa, Andrey Efimovb, Igor Bogusha, Kathy Q. Caib, Harvey H. Hensleya, Brian L. Eglestona, Andres Klein-Szantob, Tamina Seeger-Nukpezaha,2, and Erica A. Golemisa,3 Programs in aDevelopmental Therapeutics and bCancer Biology, Fox Chase Cancer Center, Philadelphia, PA 19111 Edited by Kathryn V. Anderson, Sloan–Kettering Institute, New York, NY, and approved July 30, 2014 (received for review March 25, 2014) Mutations inactivating the cilia-localized Pkd1 protein result in protrudes like an antenna from many cells. For this reason, and autosomal dominant polycystic kidney disease (ADPKD), a serious because defects in the cilium per se can result in renal cystic inherited syndrome affecting ∼1 in 500 people, in which accumula- syndromes that have some features of ADPKD (3), ADPKD is tion of renal cysts eventually destroys kidney function. Severity of classified among the ciliopathies. ADPKD varies throughout the population, for reasons thought to NEDD9 (also known as HEF1 and Cas-L) is a scaffold for cell involve differences both in intragenic Pkd1 mutations and in mod- signaling interactions that govern cell attachment and migration ifier alleles. The scaffolding protein NEDD9, commonly dysregulated (4, 5), survival (6), mitogenic signaling and cell cycle control (7– during cancer progression, interacts with Aurora-A (AURKA) kinase 10), and ciliary resorption (11, 12). To date, NEDD9 has been to control ciliary resorption, and with Src and other partners to in- most studied in the context of cancer, because deregulated ex- fluence proliferative signaling pathways often activated in ADPKD. pression of NEDD9 accompanies and promotes metastasis in We here demonstrate Nedd9 expression is deregulated in human a large and growing number of cancer types, whereas genetic ADPKD and a mouse ADPKD model. Although genetic ablation of ablation of NEDD9 has a significant modifier function for tumor Nedd9 does not independently influence cystogenesis, constitutive initiation and progression (8, 13, 14). A particularly interesting absence of Nedd9 strongly promotes cyst formation in the tamox- feature of NEDD9 action in cancer is that both overexpression + ifen-inducible Pkd1fl/fl;Cre/Esr1 mouse model of ADPKD. This cys- and loss of function have been found to be tumor promoting togenic effect is associated with striking morphological defects in different cellular contexts, likely because either form of disrup- −/− −/− the cilia of Pkd1 ;Nedd9 mice, associated with specific loss of tion of its scaffolding action impairs downstream processes. ciliary localization of adenylase cyclase III in the doubly mutant ge- Importantly, NEDD9 interacts directly with a number of sig- notype. Ciliary phenotypes imply a failure of Aurora-A activation: naling proteins that are directly relevant to functions disrupted in −/− −/− MEDICAL SCIENCES Compatible with this idea, Pkd1 ;Nedd9 mice had ciliary resorp- −/− ADPKD. NEDD9 binds and activates SRC, regulating cell mi- tion defects, and treatment of Pkd1 mice with a clinical Aurora-A gration and attachment (15–17). NEDD9 supports the activity of kinase inhibitor exacerbated cystogenesis. In addition, activation of the EGFR effector cascade, binding directly to the EGFR ef- the ADPKD-associated signaling effectors Src, Erk, and the mTOR + fector Shc1 (7, 8). Nedd9 binds and is required for activity of effector S6 was enhanced, and Ca2 response to external stimuli −/− −/− −/− Aurora-A kinase: The loss of interactions between these proteins was reduced, in Pkd1 ;Nedd9 versus Pkd1 mice. Together, induces genomic abnormalities and centrosomal defects (18, 19), these results indicated an important modifier action of Nedd9 on causes loss of ciliary resorption (12), and influences PKD2- ADPKD pathogenesis involving failure to activate Aurora-A. associated signaling (20, 21). Based on these and other findings, we have hypothesized that NEDD9 expression might have a role HEF1 | ganetespib | STA-2842 Significance utosomal dominant polycystic kidney disease (ADPKD) is Aone of the most common inherited kidney diseases, affect- This study uses mouse models for the first time to our knowl- ing 600,000 people in the United States (1). The disease is pre- edge to identify that NEDD9, a nonenzymatic scaffolding pro- dominantly characterized by the development and enlargement tein that is commonly amplified in cancer, has an important of renal cysts, as well as extrarenal systems that commonly in- restraining function for the development of renal cysts in au- clude sporadic cysts in the liver, seminal vesicles (in males), and tosomal dominant polycystic kidney disease (ADPKD). In the pancreas; hypertension; and vascular manifestations associated absence of NEDD9, failure to activate Aurora-A kinase causes with aneurysms (2). There is no specific treatment available that multiple abnormalities in cilia, intensifying the effect of genetic can prevent ADPKD progression toward end-stage renal disease deficiency of mutations in the polycystic kidney disease (PKD) 1 (ESRD), associated with a requirement for renal transplant or gene, the most common cause of PKD. As important implica- dialysis. Given the time of onset of ADPKD varies more than tions, clinical inhibitors of Aurora-A also intensified ADPKD two decades in affected families, and the disease can progress in induced by mutation of PKD1, suggesting caution in use of an indolent or aggressive manner, identifying modifier genes that these agents, whereas recently reported polymorphisms in increase or decrease the severity of ADPKD symptoms would be Nedd9 may contribute to the genetic heterogeneity of ADPKD clinically valuable. presentation in affected families. ADPKD arises from mutational inactivation of polycystin 1 and 2 (PC1 and PC2), encoded by polycystic kidney disease (PKD) 1 Author contributions: A.S.N. and E.A.G. designed research; A.S.N., O.V.P., V.S., A.E., I.B., and PKD2, two heterodimerizing transmembrane proteins that K.Q.C., and T.S.-N. performed research; H.H.H. contributed new reagents/analytic tools; A.S.N., O.V.P., I.B., K.Q.C., B.L.E., and A.K.-S. analyzed data; A.S.N., B.L.E., A.K.-S., and E.A.G. transmit extracellular mechanical and molecular cues by in- wrote the paper. 2+ creasing cellular Ca uptake and association with intracellular The authors declare no conflict of interest. signaling partners. Multiple signaling pathways are compromised This article is a PNAS Direct Submission. in ADPKD. Observed defects including elevated activity of re- 1Present address: Department of Biochemistry and Molecular Biology, Monash University, ceptor tyrosine kinases (EGFR, IGF1R, and VEGFR); activation Clayton, Victoria 3800, Australia. of the Ras-Raf-ERK proliferative signaling; elevated activity of 2Present address: Department of Internal Medicine, Center for Integrated Oncology, the Src, PKA, mTOR, and S6 kinases; and altered levels of in- University Hospital of Cologne, 50931 Cologne, Germany. 2+ tracellular cAMP and Ca , affecting numerous second messenger 3To whom correspondence should be addressed. Email: [email protected]. pathways (2). PC1 and PC2 function as a heterodimer displayed This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. on the cell membrane of the primary cilium, an organelle that 1073/pnas.1405362111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1405362111 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 −/− −/− in controlling signaling processes associated with renal cysto- and a much more extensive cystogenesis in Pkd1 ;Nedd9 −/− genesis. The results reported here indicate a striking modifier relative to Pkd1 mice (Fig. 1 C–F and Fig. S1A). In contrast, −/− function of NEDD9 and its effector Aurora-A on the process of mice with a Nedd9 genotype were comparable to wt mice in cystogenesis, mediated through regulation of both ciliary and kidney size and absence of cysts, indicating a modifier rather nonciliary signaling. than a primary function in cyst generation. Together these data indicated a physiological role of Nedd9 in control of cyst for- Results mation in the context of an initiating lesion in Pkd1. In prelimi- Nedd9 Expression Is Elevated in Renal Cysts. We first examined nary studies to compare genotypes at P15, when cystogenesis is −/− −/− −/− NEDD9 expression in kidney sections of patients diagnosed with well advanced in Pkd1 mice, we found that Pkd1 ;Nedd9 PKD. Immunohistochemical analysis of primary human kidney mice did not survive to P15, with mortality commencing at P11. specimens detected intense NEDD9 staining in the epithelial Histopathological analysis of P10 renal tissue with markers of lining of cysts. Less intense staining was also seen in cells of the proximal and distal convoluted tubules, collecting ducts, and the proximal and distal convoluted tubules, and in the collecting B C A medullary thick ascending loops of Henle (Fig. S1 and )in- ducts, but not in the glomerulus (Fig. 1 ). This expression pat- dicated that cysts originated from all three compartments in both tern is similar to that we identified for AURKA (20) and −/− −/− −/− + Pkd1 and Pkd1 ;Nedd9 mice. The larger cysts in each case reported for PC2 (22). Pkd1fl/fl;Cre/Esr1 mice induced with −/− associated with markers for collecting ducts and the loops of tamoxifen at postnatal day (P)2 and P3 (referred to as Pkd1 Henle, regardless of genotype. Ki67 staining followed by quanti-
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