Phosphorylation of C-terminal polycystin-2 influences the interaction with PIGEA14: A QCM study based on solid supported membranes

Morick, Daniela; Schatz, Michaela; Hubrich, Raphael; Hoffmeister, Helen; Krefft, Anya; Witzgall, Ralph; Steinem, Claudia

doi:10.1016/j.bbrc.2013.06.105

Cited by 7 publications

(7 citation statements)

References 35 publications

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“…This feature is observed in Na v , Ca v and in the small (SK) and large-conductance Ca 2+activated K + (BK) channels, where separate Ca 2+ -sensor proteins bind to motifs within the channel to control gating (Ben-Johny and Yue, 2014; Fanger et al, 1999;Lee and MacKinnon, 2018;Wang et al, 2014). Polycystin-2 interacts with a number of different proteins, however it is unknown if their association is Ca 2+ -dependent (Morick et al, 2013;Sammels et al, 2010;Streets et al, 2010). Recently, calmodulin was reported to bind and regulate the function of polycystin-2L1-but this relationship is undetermined for polycystin-2 regulation by any other Ca 2+ effector proteins (Park et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease

Vien

Smith

et al. 2020

Journal of Cell Science

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Approximately 15% of autosomal dominant polycystic kidney disease (ADPKD) is caused by variants in PKD2. PKD2 encodes polycystin-2, which forms an ion channel in primary cilia and endoplasmic reticulum (ER) membranes of renal collecting duct cells. Elevated internal Ca2+ modulates polycystin-2 voltage dependent gating and subsequent desensitization— two biophysical regulatory mechanisms that control its function at physiological membrane potentials. Here, we refute the hypothesis that Ca2+ occupancy of the polycytsin-2 intracellular EF hand is responsible for these forms of channel regulation, and if disrupted, results in ADPKD. We identify and introduce mutations that attenuate Ca2+-EF hand affinity but find channel function is unaltered in the primary cilia and ER membranes. We generated two new mouse strains that harbor distinct mutations that abolish Ca2+-EF hand association but do not result in a PKD phenotype. Our findings suggest additional Ca2+ binding sites within polycystin-2 or Ca2+-dependent modifiers are responsible for regulating channel activity.

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Section: Discussionmentioning

confidence: 99%

Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease

Vien

Smith

et al. 2020

Journal of Cell Science

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“…; Morick et al . ). The intraflagellar transport protein IFT57 and the serine/threonine kinase Nek8 directly bind PC2 and are important to PC2 localisation to the primary cilium.…”

Section: Overview Of Mechanosensitivitymentioning

confidence: 97%

“…The phosphorylation of a PC2 N-terminal site by GSK3 is important to its trafficking to the plasma membrane but not to the primary cilium (Streets et al 2006). Other partners, PACS1, PACS2 and PIGEA14 are important to the routing of PC2 between ER, Golgi and the plasma membrane (Köttgen et al 2005;Morick et al 2013). The intraflagellar transport protein IFT57 and the serine/threonine kinase Nek8 directly bind PC2 and are important to PC2 localisation to the primary cilium.…”

Section: Other Polycystin-interacting Partnersmentioning

confidence: 99%

Polycystins and partners: proposed role in mechanosensitivity

Retailleau

Duprat

2014

The Journal of Physiology

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Mutations of the two polycystins, PC1 and PC2, lead to polycystic kidney disease. Polycystins are able to form complexes with numerous families of proteins that have been suggested to participate in mechanical sensing. The proposed role of polycystins and their partners in the kidney primary cilium is to sense urine flow. A role for polycystins in mechanosensing has also been shown in other cell types such as vascular smooth muscle cells and cardiac myocytes. At the plasma membrane, polycystins interact with diverse ion channels of the TRP family and with stretch-activated channels (Piezos, TREKs). The actin cytoskeleton and its interacting proteins, such as filamin A, have been shown to be essential for these interactions. Numerous proteins involved in cell-cell and cell-extracellular matrix junctions interact with PC1 and/or PC2. These multimeric protein complexes are important for cell structure integrity, the transmission of force, as well as for mechanosensing and mechanotransduction. A group of polycystin partners are also involved in subcellular trafficking mechanisms. Finally, PC1 and especially PC2 interact with elements of the endoplasmic reticulum and are essential components of calcium homeostasis.In conclusion, we propose that both PC1 and PC2 act as conductors to tune the overall cellular mechanosensitivity.

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“…The attachment of their most sensitive phosphor-tag (monobiotinylated) at a concentration of 0.1 µg/ml revealed a change of around -40 Hz. Other phosphorylation studies using QCM are that of DNA phosphorylation by polynucleotide kinase [36] and the phosphorylation of polycystin-2 to obtain the binding affinities and kinetic constants of the reaction [37].…”

Section: Quartz Crystal Microbalancementioning

confidence: 99%

Biosensors for Screening Kinase Inhibitors

Bhalla

Estrela

2017

CTMC

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For successful drug discovery it is important to understand the fundamentals of the underlying causes and consequences of the diseases for which the drug is being developed. One such physiological process in eukaryotic cells is protein phosphorylation, which is the main post-translational modification of proteins responsible for the onset or progression of Alzheimer's disease, diabetes and various cancers. Protein phosphorylation is facilitated by kinases and inhibitors of kinases act as drugs in controlling or curing these diseases by reducing protein phosphorylation. This review discusses the technologies capable of detecting kinase activity and screening candidate compounds to identify novel inhibitors of protein kinases.

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Phosphorylation of C-terminal polycystin-2 influences the interaction with PIGEA14: A QCM study based on solid supported membranes

Cited by 7 publications

References 35 publications

Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease

Disrupting polycystin-2 EF hand Ca2+ affinity does not alter channel function or contribute to polycystic kidney disease

Polycystins and partners: proposed role in mechanosensitivity

Biosensors for Screening Kinase Inhibitors

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