Nedd9 restrains renal cystogenesis in Pkd1 ^−/− mice

Abstract

Significance This study uses mouse models for the first time to our knowledge to identify that NEDD9, a nonenzymatic scaffolding protein that is commonly amplified in cancer, has an important restraining function for the development of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). In the absence of NEDD9, failure to activate Aurora-A kinase causes multiple abnormalities in cilia, intensifying the effect of genetic deficiency of mutations in the polycystic kidney disease (PKD) 1 gene, the most common cause of PKD. As important implications, clinical inhibitors of Aurora-A also intensified ADPKD induced by mutation of PKD1 , suggesting caution in use of these agents, whereas recently reported polymorphisms in Nedd9 may contribute to the genetic heterogeneity of ADPKD presentation in affected families.

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

“…found that genetically induced loss of cilia in mice ameliorated cystogenesis induced by defects in either Pkd1 or Pkd2 [165]. This finding was corroborated by another study, in which administration of a drug that stabilized cilia by inhibiting the cilia disassembly-promoting kinase Aurora-A exacerbated cystogenesis caused by a mutant Pkd1 [157]. These findings suggest that significant differences might exist in the aetiology and signaling dependency of cysts originating from loss of cilia and those induced by mutation of the polycystins.…”

“…Some evidence suggests that the polycystin 1 and proteins associated with its function regulate cell migration in cancer [156] and in normal development [98]; how these processes are affected in the context of ADPKD requires further study. Proteins involved in interaction with the ECM and interpretation of ECM signals for growth, including integrins, the prometastatic protein Nedd9, and their effector, Src, are upregulated with cystogenesis, and some preclinical studies targeting these proteins suggests efficacy in reducing cyst growth [43, 44, 157, 158]. …”

“…Proteins involved in the interaction with the ECM are upregulated (SRC, integrins, NEDD9) and their inhibition impacts cystogenesis in preclinical models [43, 44, 157, 158]…”

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

“…The biological activities of NEDD9 in ADPKD reflect of its activation of the Aurora-A kinase, which induces resorption of cilia, limiting this defective signaling (Fig. 4) [104]. In addition, several recent studies implicate NEDD9 and Aurora-A with regulation by and regulation of calcium/calmodulin signaling, not only in ciliary signaling, but also in control of mitosis, which may inform the oncogenic activity of NEDD9 and Aurora-A [105–107].…”

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

“…While a thorough review is premature because insufficient numbers of molecular variants have been identified and functionally characterized, current evidence suggests considerable heterogeneity in the types of sequence variation that produce modifier effects. The studies discussed in this review provide examples of modifier variants that cause partial or complete loss of gene function (e.g., missense mutation 32,66 or gene deletion 33,40 ), enhanced function (e.g., increased protein stability 30 ), and gain of alternative function (e.g., novel protein-protein interaction 75 ). They also demonstrate that modifier variants often occur within protein-coding exons, but may alternatively affect regulatory regions such as UTRs or promoters.…”