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Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy

Core Research Laboratory–Institute for Cancer Research, Prevention and Clinical Network (ISPRO), 50139 Florence, Italy
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Cancers 2019, 11(4), 449; https://doi.org/10.3390/cancers11040449
Received: 12 February 2019 / Revised: 20 March 2019 / Accepted: 26 March 2019 / Published: 29 March 2019
(This article belongs to the Special Issue Protein Kinases and Cancers)
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Abstract

Hedgehog (HH) signaling is an evolutionarily conserved pathway that is crucial for growth and tissue patterning during embryonic development. It is mostly quiescent in the adult, where it regulates tissue homeostasis and stem cell behavior. Aberrant reactivation of HH signaling has been associated to several types of cancer, including those in the skin, brain, prostate, breast and hematological malignancies. Activation of the canonical HH signaling is triggered by binding of HH ligand to the twelve-transmembrane protein PATCHED. The binding releases the inhibition of the seven-transmembrane protein SMOOTHENED (SMO), leading to its phosphorylation and activation. Hence, SMO activates the transcriptional effectors of the HH signaling, that belong to the GLI family of transcription factors, acting through a not completely elucidated intracellular signaling cascade. Work from the last few years has shown that protein kinases phosphorylate several core components of the HH signaling, including SMO and the three GLI proteins, acting as powerful regulatory mechanisms to fine tune HH signaling activities. In this review, we will focus on the mechanistic influence of protein kinases on HH signaling transduction. We will also discuss the functional consequences of this regulation and the possible implications for cancer therapy. View Full-Text
Keywords: Hedgehog; GLI; Smoothened; protein kinases; phosphorylation; cancer; targeted therapy Hedgehog; GLI; Smoothened; protein kinases; phosphorylation; cancer; targeted therapy
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Montagnani, V.; Stecca, B. Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy. Cancers 2019, 11, 449.

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