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.
Highlights
Hedgehog (HH) signaling is a highly conserved pathway playing an essential role in embryonic development, tissue homeostasis and stem cell maintenance
The protein kinase C (PKC) proteins are widely expressed serine/threonine kinases. They consist of three families: calcium-dependent conventional PKC; calciumindependent novel PKC; and calcium-independent atypical PKC
This study provided the first evidence that the atypical PKC (aPKC)-histone deacetylase 1 (HDAC1) axis can be efficiently blocked in basal cell carcinoma (BCC) using this aPKC antagonist in combination with the HDAC inhibitor vorinostat, providing an effective and novel therapeutic approach for BCC patients [162]
Summary
Hedgehog (HH) signaling is a highly conserved pathway playing an essential role in embryonic development, tissue homeostasis and stem cell maintenance. The activity of the HH pathway has to be tightly controlled at multiple levels. Protein phosphorylation is the most investigated post-translational modification, and it is mediated by protein kinases (PK) and protein phosphatases [2]. Phosphorylation status of a protein is controlled by a balance between kinase and phosphatase activities, and affects protein conformation, stability, activity and interaction with other proteins [3]. The activity of the HH signaling is regulated by a number of phosphorylation events that occur mainly at the level of the G-protein coupled-receptor (GPCR). We will review studies of PKs involved in the regulation of the HH signaling with a focus on cancer. We will discuss the mechanistic and functional consequences that phosphorylation events play in HH signaling transduction and the implications for cancer therapy
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