Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in
            <i>Drosophila</i>

Jiang, Kai; Liu, Yajuan; Fan, Junping; Epperly, Garretson; Gao, Tianyan; Jen, Jin; Jia, Jianhang

doi:10.1073/pnas.1417147111

Cited by 34 publications

(43 citation statements)

References 52 publications

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“…Additionally, studies of basal cell carcinomas revealed that Prkci can phosphorylate and activate Gli1, thereby potentiating Hh signaling (Atwood et al, 2013). Similarly, in flies, aPKC, a Prkci homolog, can phosphorylate and activate Smo and the Gli homolog Ci, leading to expression of Hh target genes, including aPKC (Jiang et al, 2014b). Thus, the apical Par polarity protein complex might regulate Hh signaling directly, via Gli1 activation, and indirectly, via modulation of cilia dynamics.…”

Section: Discussionmentioning

confidence: 99%

miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

et al. 2016

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The transition of dividing neuroepithelial progenitors to differentiated neurons and glia is essential for the formation of a functional nervous system. Sonic hedgehog (Shh) is a mitogen for spinal cord progenitors, but how cells become insensitive to the proliferative effects of Shh is not well understood. Because Shh reception occurs at primary cilia, which are positioned within the apical membrane of neuroepithelial progenitors, we hypothesized that loss of apical characteristics reduces the Shh signaling response, causing cell cycle exit and differentiation. We tested this hypothesis using genetic and pharmacological manipulation, gene expression analysis and time-lapse imaging of zebrafish embryos. Blocking the function of miR-219, a microRNA that downregulates apical Par polarity proteins and promotes progenitor differentiation, elevated Shh signaling. Inhibition of Shh signaling reversed the effects of miR-219 depletion and forced expression of Shh phenocopied miR-219 deficiency. Time-lapse imaging revealed that knockdown of miR-219 function accelerates the growth of primary cilia, revealing a possible mechanistic link between miR-219-mediated regulation of apical Par proteins and Shh signaling. Thus, miR-219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving these cells towards differentiation.

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Section: Discussionmentioning

confidence: 99%

miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

et al. 2016

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“…Drosophila S2 cells 54 were transfected with ub-Gal4, UAST-NT, and individual dsRNAs 55 to inhibit the expression of NTR-like receptors CG9918 (nucleotides 11~570), CG8784 (nucleotides −72~478), CG8795 (nucleotides −203~343), Capa (nucleotides 1–455) or GFP control (nucleotides 6–606) using Effectene (Qiagen). Cells (6 x 10 6 ) were dissolved in lysis buffer (450 μL) 48h post-transfection, microcentrifuged (12000 rpm, 10min), and supernatants were analyzed by western blotting.…”

Section: Methodsmentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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“…The extent of phosphorylation of the PKA/ CKI clusters depends on HH levels and controls in a graded manner SMO clustering, the degree of conformational change in its cytotail, its accumulation at the cell surface and its signaling activity Su et al, 2011;Zhao et al, 2007). Moreover, CKIγ/Gilgamesh (Gish), G-protein-coupled receptor kinase 2 (GPRK2/GRK2), Casein kinase II and atypical protein kinase C increase the ability of SMO to transduce high levels of HH by phosphorylating residues present in the membrane-proximal and central regions of the SMO cyto-tail (Jia et al, 2010;Jiang et al, 2014;Li et al, 2016;Maier et al, 2014). In vertebrates, SMO phosphorylation has been reported to depend on GRK2 and CKIγ (Chen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused

et al. 2017

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Smoothened (SMO) is a G-protein-coupled receptor-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is a central unsolved issue. Using the wing imaginal disc model in Drosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity. Surprisingly, phosphorylation at these sites is induced by the kinase Fused (FU), a known downstream effector of SMO. In turn, activation of SMO induces FU to act on its downstream targets. Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikinase phosphorylation cascade. We propose that this complex interplay amplifies signaling above a threshold that allows high HH signaling.

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Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in Drosophila

Cited by 34 publications

References 52 publications

miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

An obligatory role for neurotensin in high-fat-diet-induced obesity

Dose-dependent transduction of Hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor Smoothened and the kinase Fused

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