Dataset Information

Novel roles of PRK1 and PRK2 in cilia and cancer biology.

ABSTRACT: PRK1 and PRK2 are two closely related AGC-family serine/threonine protein kinases. Here we demonstrate novel roles for them at cilia and in cancer biology. In both instances serum withdrawal leads to increased activating PRK1 and PRK2 phosphorylation (pPRK1/pPRK2) and their depletion results in reduced spheroid growth. pPRK1/pPRK2 localise to the transition zone of cilia and their co-depletion results in reduced cilia size, impaired planer polarity and impaired cilia associated signalling. High PRK2 (but not PRK1) expression correlates with poor outcome in patients with basal-like/Triple Negative (TN) Breast Cancer (BC) where there is also higher expression relative to other BC tumour subtypes. In agreement, depletion of PRK1 and PRK2 in mouse TNBC cells, or CRISPR/Cas9 mediated deletion of PRK2 alone, significantly reduces cell proliferation and spheroid growth. Finally proteomic analysis to identify PRK2 binding partners in mouse TNBC cells revealed proteins that are important for both cilia and BC biology. Taken together these data demonstrate novel roles for PRK1 and PRK2 at cilia and in BC biology and in the case of PRK2 in particular, identifies it as a novel TNBC therapeutic target.

SUBMITTER: Patel H

PROVIDER: S-EPMC7054267 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Novel roles of PRK1 and PRK2 in cilia and cancer biology.

Patel Hitesh H Li Jun J Herrero Ana A Kroboth Jakob J Byron Adam A Kriegsheim Alex Von AV Brunton Valerie V Carragher Neil N Hurd Toby T Frame Margaret M

Scientific reports 20200303 1

PRK1 and PRK2 are two closely related AGC-family serine/threonine protein kinases. Here we demonstrate novel roles for them at cilia and in cancer biology. In both instances serum withdrawal leads to increased activating PRK1 and PRK2 phosphorylation (pPRK1/pPRK2) and their depletion results in reduced spheroid growth. pPRK1/pPRK2 localise to the transition zone of cilia and their co-depletion results in reduced cilia size, impaired planer polarity and impaired cilia associated signalling. High ...[more]

PMID: 32127582

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Project description:UnlabelledBackgroundThe primary cilium is a microtubule-based, plasma membrane-ensheathed protrusion projecting from the basal bodies of almost all cell types in the mammalian body. In the past several years a plethora of papers has indicated a crucial role for primary cilia in the development of a wide variety of organs. We have investigated heart development in cobblestone, a hypomorphic allele of the gene encoding the intraflagellar transport protein Ift88, and uncovered a number of the most common congenital heart defects seen in newborn humans.MethodsWe generated serial sections of mutant cobblestone and wild type embryos in the region encompassing the heart and the cardiac outflow tract. The sections were further processed to generate three-dimensional reconstructions of these structures, and immunofluorescence confocal microscopy, transmission electron microscopy, and in situ hybridization were used to examine signal transduction pathways in the relevant areas. Whole mount in situ hybridization was also employed for certain developmental markers.ResultsIn addition to an enlarged pericardium and failure of both ventricular and atrial septum formation, the cobblestone mutants displayed manifold defects in outflow tract formation, including persistent truncus arteriosus, an overriding aorta, and abnormal transformation of the aortic arches. To discern the basis of these anomalies we examined both the maintenance of primary cilia as well as endogenous and migratory embryonic cell populations that contribute to the outflow tract and atrioventricular septa. The colonization of the embryonic heart by cardiac neural crest occurred normally in the cobblestone mutant, as did the expression of Sonic hedgehog. However, with the loss of primary cilia in the mutant hearts, there was a loss of both downstream Sonic hedgehog signaling and of Islet 1 expression in the second heart field, a derivative of the pharyngeal mesoderm. In addition, defects were recorded in development of atrial laterality and ventricular myocardiogenesis. Finally, we observed a reduction in expression of Bmp4 in the outflow tract, and complete loss of expression of both Bmp2 and Bmp4 in the atrioventricular endocardial cushions. Loss of BMP2/4 signaling may result in the observed proliferative defect in the endocardial cushions, which give rise to both the atrioventricular septa as well as to the septation of the outflow tract.ConclusionsTaken together, our results potentially identify a novel link between Sonic hedgehog signaling at the primary cilium and BMP-dependent effects upon cardiogenesis. Our data further point to a potential linkage of atrioventricular septal defects, the most common congenital heart defects, to genes of the transport machinery or basal body of the cilia.

Dataset Information

Novel roles of PRK1 and PRK2 in cilia and cancer biology.

Publications

Novel roles of PRK1 and PRK2 in cilia and cancer biology.

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