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

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.

Keywords: GLI; Hedgehog; Smoothened; cancer; phosphorylation; protein kinases; targeted therapy.

Figure 1

Overview of Hedgehog pathway in absence (a) and in presence (b) of HH ligand. Schematic diagram of the basic components of the HH signaling (filled circles) and protein kinases that act as positive (green) or negative (red) regulators. GLI2 and GLI3 move within the PC together with KIF7, a member of the kinesin family of anterograde motor proteins. See main text for details. Abbreviations: PTCH1, Patched 1; SMO, Smoothened; SUFU, Suppressor of Fused; HH, Hedgehog; KIF7, kinesin family member 7; CK1, caseine kinase 1; CK2, casein kinase 2; GSK3β, glycogen synthase kinase 3β; PKA, protein kinase A; ULK3, Unc-51 like kinase 3; GRK2, G-protein coupled receptor kinase 2; S6K1, ribosomal protein S6 kinase 1; AKT, protein kinase B; ERK1/2, extracellular signal-regulated kinases 1/2; DYRK, dual specificity tyrosine-phosphorylation-regulated kinase; aPKCι/λ, atypical protein kinase Cι/λ; AMPK, AMP-activated protein kinase; MEKK2/3, mitogen-activated protein kinase kinase kinase 2/3; PLK1, polo-like kinase 1.

Figure 2

Targeting the Hedgehog pathway. Inhibition of the HH pathway by direct SMO and GLI inhibitors (red boxes) and by small molecules or drugs targeting protein kinases. Indicated are protein kinases that act as negative regulators (red) and positive regulators (green) of the GLI. For each protein kinase agonists and antagonists are reported. For details regarding the inhibitors and their target or mechanism of action see Table 1. Abbreviations: SMO, Smoothened; PTCH, Patched; KIF7, kinesin family member 7; HH, Hedgehog; GLI1/2^A, GLI1/2 activators; CK1α, casein kinase 1α; CK2, casein kinase 2; PKA, protein kinase A; S6K1, ribosomal protein S6 kinase 1; PI3K, phosphatidylinositol-3-kinase; DYRK1B, dual specificity tyrosine-phosphorylation-regulated kinase 1B; aPKCι/λ, atypical protein kinase ι/λ; BRD4, bromodomain-containing protein 4.