The emerging roles of phosphatases in Hedgehog pathway

Zhao, Long; Wang, Liguo; Chi, Chunli; Lan, Wenwen; Su, Ying

doi:10.1186/s12964-017-0191-0

Cited by 27 publications

(16 citation statements)

References 116 publications

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“…SMO-bound PKA-C cannot access soluble GLI substrates. This leads to loss of inhibitory GLI phosphorylation, which could occur via GLI protein turnover (Hui and Angers, 2011;Humke et al, 2010;Niewiadomski et al, 2013), tonic action of phosphatases on GLI (Zhao et al, 2017), or both. Our proposed mechanism helps to explain key aspects of SMO-to-GLI communication not easily reconciled with existing models.…”

Section: Discussionmentioning

confidence: 99%

Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits

Arveseth

Happ

Hedeen

et al. 2020

Preprint

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ABSTRACTThe Hedgehog (Hh) pathway is essential for organ development, homeostasis, and regeneration. Dysfunction of this cascade drives several cancers. To control expression of pathway target genes, the G protein-coupled receptor (GPCR) Smoothened (SMO) activates glioma-associated (GLI) transcription factors via an unknown mechanism. Here we show that, rather than conforming to traditional GPCR signaling paradigms, SMO activates GLI by binding and sequestering protein kinase A (PKA) catalytic subunits at the membrane. This sequestration, triggered by GPCR kinase 2 (GRK2)-mediated phosphorylation of SMO intracellular domains, prevents PKA from phosphorylating soluble substrates, releasing GLI from PKA-mediated inhibition. Our work provides a mechanism directly linking Hh signal transduction at the membrane to GLI transcription in the nucleus. This process is more fundamentally similar between species than prevailing hypotheses suggest. The mechanism described here may apply broadly to other GPCR- and PKA-containing cascades in diverse areas of biology.

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Section: Discussionmentioning

confidence: 99%

Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits

Arveseth

Happ

Hedeen

et al. 2020

Preprint

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“…In addition to Sufu, several core components of Hedgehog pathway undergo reversible phosphorylation mediated by protein kinases and phosphatases, which acts as an effective regulatory mechanism to modulate Hedgehog signal activities 39 . It has been well established that multiple sites’ phosphorylation on Ci/Gli by PKA, PKA-primed CK1, or PKA-primed GSK3 facilitates the production of truncated transcriptional repressor CiR/GliR through proteolytic processing 40 – 43 .…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused

et al. 2020

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Reversible phosphorylation of Suppressor of fused (Sufu) is essential for Sonic Hedgehog (Shh) signal transduction. Sufu is stabilized under dual phosphorylation of protein kinase A (PKA) and glycogen synthase kinase 3β (GSK3β). Its phosphorylation is reduced with the activation of Shh signaling. However, the phosphatase in this reversible phosphorylation has not been found. Taking advantage of a proteomic approach, we identified Protein phosphatase 4 regulatory subunit 2 (Ppp4r2), an interacting protein of Sufu. Shh signaling promotes the interaction of these two proteins in the nucleus, and Ppp4 also promotes dephosphorylation of Sufu, leading to its degradation and enhancing the Gli1 transcriptional activity. Finally, Ppp4-mediated dephosphorylation of Sufu promotes proliferation of medulloblastoma tumor cells, and expression of Ppp4 is positively correlated with up-regulation of Shh pathway target genes in the Shh-subtype medulloblastoma, underscoring the important role of this regulation in Shh signaling.

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“…The pathway is initiated by the binding of Hh with its receptor Patched (Ptc). G-protein-coupled receptor Smoothened (Smo) is activated to prevent phosphorylation and proteolysis of the transcription factor Cubitus interruptus (Ci), which eventually translocates into the nucleus to switch on target gene expressions [ 54 ]. In the lymph gland, Hh signaling is crucial for the maintenance of blood cell progenitors in MZ.…”

Section: Regulatory Signaling During Lymph Gland Developmentmentioning

confidence: 99%

Regulation of Drosophila Hematopoiesis in Lymph Gland: From a Developmental Signaling Point of View

Lan

Liu

Zhao

et al. 2020

IJMS

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The Drosophila hematopoietic system is becoming increasingly attractive for its simple blood cell lineage and its developmental and functional parallels with the vertebrate system. As the dedicated organ for Drosophila larval hematopoiesis, the lymph gland harbors both multipotent stem-like progenitor cells and differentiated blood cells. The balance between progenitor maintenance and differentiation in the lymph gland must be precisely and tightly controlled. Multiple developmental signaling pathways, such as Notch, Hedgehog, and Wnt/Wingless, have been demonstrated to regulate the hematopoietic processes in the lymph gland. Focusing on blood cell maintenance and differentiation, this article summarizes the functions of several classic developmental signaling pathways for lymph gland growth and patterning, highlighting the important roles of developmental signaling during lymph gland development as well as Drosophila larval hematopoiesis.

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The emerging roles of phosphatases in Hedgehog pathway

Cited by 27 publications

References 116 publications

Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits

Smoothened Transduces Hedgehog Signals via Activity-Dependent Sequestration of PKA Catalytic Subunits

Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused

Regulation of Drosophila Hematopoiesis in Lymph Gland: From a Developmental Signaling Point of View

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