Dishevelled Paralogs in Vertebrate Development: Redundant or Distinct?

Gentzel, Marc; Schambony, Alexandra

doi:10.3389/fcell.2017.00059

Cited by 24 publications

(21 citation statements)

References 81 publications

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“…Interestingly, even though DVL-1 is one of the least abundant of the total DVL protein pool, it has been shown to play an imperative role in stimulating LRP6 phosphorylation and activation of the Wnt transcriptional activity 11,12 . DVL is not only critical in human development 13 and key physiological processes, but its altered expression has been demonstrated in some tumours relative to non-transformed cells and linked with various cancer types 3,14,15 . Even though DVL proteins bridge critical Wnt signals with nuclear responses, how it is regulated is poorly understood 16 .…”

Section: Introductionmentioning

confidence: 99%

Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer

Sharma

Molehin

Castro‐Piedras

et al. 2019

Sci Rep

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Dishevelled (DVL) proteins are central mediators of the Wnt signalling pathway and are versatile regulators of several cellular processes, yet little is known about their post-translational regulation. Acetylation is a reversible post-translational modification (PTM) which regulates the function of several non-histone proteins involved in tumorigenesis. Since we previously demonstrated that lysine deacetylase, SIRT-1, regulates DVL protein levels and its function, we reasoned that DVL could potentially be a substrate for SIRT-1 mediated deacetylation. To further examine the potential role of multiple families of lysine deacetylases in the post-translational regulation of DVL, we screened for novel acetylation sites using liquid chromatography mass-spectrometry (LC-MS/MS) analysis. Herein, we report 12 DVL-1 lysine residues that show differential acetylation in response to changes in oxygen tension and deacetylase inhibition in triple-negative breast cancer (TNBC). PTMs are well documented to influence protein activity, and cellular localization. We also identify that acetylation of two key lysine residues, K69 and K285, present on the DIX and PDZ domains respectively, promote nuclear over cytoplasmic localization of DVL-1, and influences its promoter binding and regulation of genes implicated in cancer. Collectively, these findings for the first time, uncover acetylation as a novel layer of regulation of DVL-1 proteins.

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Section: Introductionmentioning

confidence: 99%

Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer

Sharma

Molehin

Castro‐Piedras

et al. 2019

Sci Rep

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“…Wnt signals are transduced via the membrane receptor Frizzled (FZD) and the intracellular protein Dishevelled (Dsh in Drosophila , DVL1–3 in humans). There is a general agreement based on strong genetic evidence in Drosophila 3 and mouse 5,6 that DVL protein(s) plays a crucial role in all major branches of Wnt signaling and serves as a signaling hub.…”

Section: Introductionmentioning

confidence: 99%

Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1

et al. 2019

Self Cite

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Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.

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“…Studies have shown that Dishevelled proteins, such as Dvl1, Dvl2, and Dvl3, act as adaptors (or scaffold proteins) that are working in partnership with Fzd (an integral membrane protein) to create the PCP protein complex of Fzd/Dvl, which in turn induces Wnt signaling downstream, having a crucial role to support development, tissue regeneration, cellular homeostasis, and an array of other cellular processes 46–48 . However, the precise biological function of Dvl proteins remains a mystery after more than two decades of studies 49 .…”

Section: Discussionmentioning

confidence: 99%

Planar cell polarity protein Dishevelled 3 (Dvl3) regulates ectoplasmic specialization (ES) dynamics in the testis through changes in cytoskeletal organization

Mao

Yan

et al. 2019

Cell Death Dis

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In the mammalian testes, such as in rats, the directional alignment of polarized elongating/elongated spermatids, in particular step 17–19 spermatids, across the plane of seminiferous epithelium resembles planar cell polarity (PCP) found in hair cells of the cochlea. It is obvious that spermatid PCP is necessary to support the simultaneous development of maximal number of elongating/elongated spermatids to sustain the daily production of > 50 million sperm per adult rat. Studies have shown that the testis indeed expresses multiple PCP proteins necessary to support spermatid PCP. Herein, using physiological and biochemical assays, and morphological analysis, and with the technique of RNA interference (RNAi) to knockdown PCP protein Dishevelled (Dvl) 1 (Dvl1), Dvl2, Dvl3, or Dvl1/2/3, Dvl proteins, in particular Dvl3, it was shown that Dvl3 played a crucial role of support Sertoli cell tight junction (TJ)-permeability barrier function through changes in the organization of actin- and microtubule (MT)-based cytoskeletons. More important, an in vivo knockdown of Dvl1/2/3 in the testis, defects of spermatid polarity were remarkably noted across the seminiferous epithelium, concomitant with defects of spermatid adhesion and spermatid transport, leading to considerably defects in spermatogenesis. More important, Dvl1/2/3 triple knockdown in the testis also impeded the organization of actin- and MT-based cytoskeletons owing to disruptive spatial expression of actin- and MT-regulatory proteins. In summary, PCP Dishevelled proteins, in particular, Dvl3 is a regulator of Sertoli cell blood–testis barrier (BTB) and also spermatid PCP function through its effects on the actin- and MT-based cytoskeletons in Sertoli cells.

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Dishevelled Paralogs in Vertebrate Development: Redundant or Distinct?

Cited by 24 publications

References 81 publications

Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer

Acetylation of conserved DVL-1 lysines regulates its nuclear translocation and binding to gene promoters in triple-negative breast cancer

Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1

Planar cell polarity protein Dishevelled 3 (Dvl3) regulates ectoplasmic specialization (ES) dynamics in the testis through changes in cytoskeletal organization

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