Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus

Wang, Gelin; Wang, Bing; Jen, Jin

doi:10.1101/gad.13.21.2828

Cited by 170 publications

(154 citation statements)

References 54 publications

(85 reference statements)

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“…Similar results were obtained when PKA was inactivated by expressing a mutant form of the PKA regulatory subunit (MS > R*) (Fig. S1) (39), because PKA also plays a dual role in Hh signaling by regulating both Ci processing and Smo activation (34,39,42). Of note, CRL also affected Hh-independent en expression in posterior (P) compartment cells as observed previously (Fig.…”

Section: Significancesupporting

confidence: 72%

Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator

Shi¹,

Li²,

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Hedgehog (Hh) signaling governs many developmental processes by regulating the balance between the repressor (Ci R /Gli R ) and activator (Ci A /Gli A ) forms of Cubitus interruptus (Ci)/gliomaassociated oncogene homolog (Gli) transcription factors. Although much is known about how Ci R /Gli R is controlled, the regulation of Ci A /Gli A remains poorly understood. Here we demonstrate that Casein kinase 1 (CK1) sustains Hh signaling downstream of Costal2 and Suppressor of fused (Sufu) by protecting Ci A from premature degradation. We show that Hh stimulates Ci phosphorylation by CK1 at multiple Ser/Thr-rich degrons to inhibit its recognition by the Hh-induced MATH and BTB domain containing protein (HIB), a substrate receptor for the Cullin 3 family of E3 ubiquitin ligases. In Hh-receiving cells, reduction of CK1 activity accelerated HIB-mediated degradation of Ci A , leading to premature loss of pathway activity. We also provide evidence that Gli A is regulated by CK1 in a similar fashion and that CK1 acts downstream of Sufu to promote Sonic hedgehog signaling. Taken together, our study not only reveals an unanticipated and conserved mechanism by which phosphorylation of Ci/Gli positively regulates Hh signaling but also provides the first evidence, to our knowledge, that substrate recognition by the Cullin 3 family of E3 ubiquitin ligases is negatively regulated by a kinase.

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Section: Significancesupporting

confidence: 72%

Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator

Shi¹,

Li²,

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…1c). Shh induction of D3, and of WSB-1 and Ptch, was completely reversed by treatments with forskolin or with the specific smoothened inhibitor cyclopamine, which both inhibit Shh signaling (19,20) (Fig. 1 c and d and data not shown).…”

Section: Resultsmentioning

confidence: 92%

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Dentice

Luongo

Huang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

150

139

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The Sonic hedgehog (Shh) pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas (BCCs), the most common human malignancy. Type 3 iodothyronine deiodinase (D3), the thyroid hormone-inactivating enzyme, is frequently expressed in proliferating and neoplastic cells, but its role in this context is unknown. Here we show that Shh, through Gli2, directly induces D3 in proliferating keratinocytes and in mouse and human BCCs. We demonstrate that Gli-induced D3 reduces intracellular active thyroid hormone, thus resulting in increased cyclin D1 and keratinocyte proliferation. D3 knockdown caused a 5-fold reduction in the growth of BCC xenografts in nude mice. Shh-induced thyroid hormone degradation via D3 synergizes with the Shh-mediated reduction of the type 2 deiodinase, the thyroxine-activating enzyme, and both effects are reversed by cAMP. This previously unrecognized functional cross-talk between Shh/Gli2 and thyroid hormone in keratinocytes is a pathway by which Shh produces its proliferative effects and offers a potential therapeutic approach to BCC.basal cell carcinoma ͉ thyroxine ͉ differentiation ͉ cancer T hyroid hormone action is regulated by the activity of the deiodinases. Type 2 deiodinase (D2) activates the prohormone thyroxine (T4) by converting it to thyroid hormone (T3), whereas D3, by inactivating T3, terminates thyroid hormone action (1). All vertebrates express D2 and D3 that, in adults, contribute to plasma T3 and T4 homeostasis by their concerted actions with the hypothalamic-pituitary feedback axis. This homeostatic mechanism is possible because the Dio3 gene is transcriptionally stimulated by T3, whereas D2 is inhibited by two thyroid hormone-mediated effects, a transcriptional downregulation of Dio2 as well as protein inactivation by ubiquitination (for review, see ref.2). During development, preprogrammed changes in D2 and D3 expression are thought to regulate intracellular T3 concentrations essential to the normal development of the central nervous system, including the retina and the inner ear (3-6). However, the signals governing the changes in D2 and D3 expression during these complex processes are largely unknown.New insight into the developmental regulation of deiodinase expression has recently been obtained in the chicken growth plate, where Indian hedgehog induces WSB-1, an E3 ubiquitin ligase adaptor that inactivates D2 (7). The hedgehog pathway, acting through the Gli family of transcription factors, determines patterns of cell growth and differentiation in a wide variety of developmental settings (8-13). Given that, in general, signals regulating D2 expression affect D3 in a reciprocal fashion (2), we hypothesized that hedgehog proteins could up-regulate D3 while suppressing D2 expression. To explore this possibility, we turned to skin, a system in which Sonic hedgehog (Shh) is known to play dominant physiological as well as pathological roles (14). Both D2 and D3 are present in skin, a well recognized target of thyroid hormone...

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“…The enhanced activator form of Ci, Ci*, has been proposed to function in wing imaginal discs of late third instar larvae. Its function requires the highest level of Hh stimulation and is dependent on Cos2, Fu and PKA [67,68]. Conversion of Ci to Ci* is not presently understood.…”

Section: Cubitus Interruptusmentioning

confidence: 99%

Regulation of Hedgehog signaling: a complex story

Ogden

Ascano

Stegman

et al. 2004

Biochemical Pharmacology

101

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The Hedgehog (Hh) signal transduction pathway plays critical instructional roles during development. Activating mutations in human Hh signaling components predispose to a variety of tumor types, and have been observed in sporadic tumors occurring in a wide range of organs. Multiple insights into the regulation of Hh signaling have been achieved through studies using Drosophila melanogaster as a model organism. In Drosophila, regulation of the transcription factor

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Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus

Cited by 170 publications

References 54 publications

Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator

Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator

Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes

Regulation of Hedgehog signaling: a complex story

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