Phosphorylation of Kif26b Promotes Its Polyubiquitination and Subsequent Proteasomal Degradation during Kidney Development

Terabayashi, Takeshi; Sakaguchi, Masaji; Shinmyozu, Kaori; Ohshima, Toshio; Johjima, Ai; Ogura, Teru; Miki, Hiroaki; Nishinakamura, Ryuichi

doi:10.1371/journal.pone.0039714

Cited by 25 publications

(24 citation statements)

References 58 publications

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“…To demonstrate the utility of KIF26B-C as a biochemical tool for dissecting the WNT5A-KIF26B signaling cascade, we tested several candidate molecules, focusing on the role of kinases. Glycogen synthase kinase 3 (GSK3), casein kinase (CK) and cyclin-dependent kinase (CDK) were previously implicated in WNT5A signaling or KIF26B regulation, but whether these kinases are specifically involved in WNT5A-dependent degradation of KIF26B has not been tested [ 23 , 24 , 25 , 26 ]. To investigate the role of these candidate kinases, we applied pharmacological inhibitors of these kinases to the GFP-KIF26B-C reporter cells and assessed the effects of these treatments on the ability of WNT5A to induce reporter degradation.…”

Section: Resultsmentioning

confidence: 99%

“…It is interesting to note that Terabayashi and colleagues previously reported that the C-terminus of KIF26B mediates CDK-induced degradation of KIF26B [ 26 ]. In addition, the authors demonstrated that CDK-dependent phosphorylation of two specific amino acid residues in KIF26B, Thr-1859 and Ser-1962, promotes the recruitment of the E3 ubiquitin ligase Nedd4 to KIF26B [ 26 ]. Collectively, this study and our present study support the crucial role of the KIF26B C-terminus in determining the stability of the KIF26B protein.…”

Section: Discussionmentioning

confidence: 99%

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Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B

Karuna

Choi

Scales

et al. 2018

Genes

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Noncanonical WNT pathways function independently of the β-catenin transcriptional co-activator to regulate diverse morphogenetic and pathogenic processes. Recent studies showed that noncanonical WNTs, such as WNT5A, can signal the degradation of several downstream effectors, thereby modulating these effectors’ cellular activities. The protein domain(s) that mediates the WNT5A-dependent degradation response, however, has not been identified. By coupling protein mutagenesis experiments with a flow cytometry-based degradation reporter assay, we have defined a protein domain in the kinesin superfamily protein KIF26B that is essential for WNT5A-dependent degradation. We found that a human disease-causing KIF26B mutation located at a conserved amino acid within this domain compromises the ability of WNT5A to induce KIF26B degradation. Using pharmacological perturbation, we further uncovered a role of glycogen synthase kinase 3 (GSK3) in WNT5A regulation of KIF26B degradation. Lastly, based on the identification of the WNT5A-responsive domain, we developed a new reporter system that allows for efficient profiling of WNT5A-KIF26B signaling activity in both somatic and stem cells. In conclusion, our study identifies a new protein domain that mediates WNT5A-dependent degradation of KIF26B and provides a new tool for functional characterization of noncanonical WNT5A signaling in cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B

Karuna

Choi

Scales

et al. 2018

Genes

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“…It is also possible that phosphorylation of Kif26b by other cellular kinases is involved in Wnt5a-dependent regulation of Kif26b. Interestingly, a previous study showed that cyclin-dependent kinase (CDK) phosphorylates Kif26b on multiple serine and threonine sites and that these phosphorylation events play a critical role in controlling the stability of Kif26b by recruiting the E3 ubiquitin ligase Nedd4 ( Terabayashi et al, 2012 ). It will be important in future studies to test whether these mechanisms, as well as the additional phosphorylation sites identified in our proteomic screens, are required for Wnt5a regulation of Kif26b degradation.…”

Section: Discussionmentioning

confidence: 99%

Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates

Susman

Karuna

Kunz

et al. 2017

eLife

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Wnt5a-Ror signaling constitutes a developmental pathway crucial for embryonic tissue morphogenesis, reproduction and adult tissue regeneration, yet the molecular mechanisms by which the Wnt5a-Ror pathway mediates these processes are largely unknown. Using a proteomic screen, we identify the kinesin superfamily protein Kif26b as a downstream target of the Wnt5a-Ror pathway. Wnt5a-Ror, through a process independent of the canonical Wnt/β-catenin-dependent pathway, regulates the cellular stability of Kif26b by inducing its degradation via the ubiquitin-proteasome system. Through this mechanism, Kif26b modulates the migratory behavior of cultured mesenchymal cells in a Wnt5a-dependent manner. Genetic perturbation of Kif26b function in vivo caused embryonic axis malformations and depletion of primordial germ cells in the developing gonad, two phenotypes characteristic of disrupted Wnt5a-Ror signaling. These findings indicate that Kif26b links Wnt5a-Ror signaling to the control of morphogenetic cell and tissue behaviors in vertebrates and reveal a new role for regulated proteolysis in noncanonical Wnt5a-Ror signal transduction.

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“…Earlier, it was reported that at this site, integrin α8β1 is localized, which binds to nephronectin on the basal lamina covering epithelial stem cells [ 49 – 51 ]. In addition, the micro-tubule-dependent motor protein kinesin (KIF26B) is established here to control cell attraction, signal transduction, and developmental patterning [ 52 – 54 ].…”

Section: Reviewmentioning

confidence: 99%

Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone

Minuth

2017

Mol Cell Pediatr

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Numerous investigations are dealing with anlage of the mammalian kidney and primary development of nephrons. However, only few information is available about the last steps in kidney development leading at birth to a downregulation of morphogen activity in the nephrogenic zone and to a loss of stem cell niches aligned beyond the organ capsule. Surprisingly, these natural changes in the developmental program display similarities to processes occurring in the kidneys of preterm and low-birth-weight babies. Although those babies are born at a time with a principally intact nephrogenic zone and active niches, a high proportion of them suffers on impairment of nephrogenesis resulting in oligonephropathy, formation of atypical glomeruli, and immaturity of parenchyma. The setting points out that up to date not identified noxae in the nephrogenic zone hamper primary steps of parenchyma development. In this situation, a possible therapeutic aim is to prolong nephrogenesis by medications. However, actual data provide information that administration of drugs is problematic due to an unexpectedly complex microanatomy of the nephrogenic zone, in niches so far not considered textured extracellular matrix and peculiar contacts between mesenchymal cell projections and epithelial stem cells via tunneling nanotubes. Thus, it remains to be figured out whether disturbance of morphogen signaling altered synthesis of extracellular matrix, disturbed cell-to-cell contacts, or modified interstitial fluid impair nephrogenic activity. Due to most unanswered questions, search for eligible drugs prolonging nephrogenesis and their reliable administration is a special challenge for the future.

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Phosphorylation of Kif26b Promotes Its Polyubiquitination and Subsequent Proteasomal Degradation during Kidney Development

Cited by 25 publications

References 58 publications

Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B

Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B

Kinesin superfamily protein Kif26b links Wnt5a-Ror signaling to the control of cell and tissue behaviors in vertebrates

Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone

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