Fig. 6. Proposed model for interaction between the PTHrP and HH signalling pathways. Signalling by all mammalian HH proteins is mediated by the Gli family of transcription factors that consist of three members: Gli1, Gli2 and Gli3. Although all Gli proteins harbour consensus PKA phosphorylation sites, only Gli2 and Gli3 are known to be functionally converted to transcriptional repressors following phosphorylation by PKA. A plausible scenario for PTHrP to antagonize HH would be through activation of PKA via PTHR1. PKA may differentially phosphorylate Gli2 or Gli3, consequently converting them to repressors and causing downregulation of some HH target genes (ALP, Col2a1, Col10a1, PTHR1) while not affecting others (Ptc). HH, in turn, may antagonize PKA activation, possibly through functional inhibition of PTHR1, thereby ensuring its own continued signalling capability.

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