PKA inhibits WNT signalling in adrenal cortex zonation and prevents malignant tumour development

Nat Commun. 2016 Sep 14;7:12751. doi: 10.1038/ncomms12751.


Adrenal cortex physiology relies on functional zonation, essential for production of aldosterone by outer zona glomerulosa (ZG) and glucocorticoids by inner zona fasciculata (ZF). The cortex undergoes constant cell renewal, involving recruitment of subcapsular progenitors to ZG fate and subsequent lineage conversion to ZF identity. Here we show that WNT4 is an important driver of WNT pathway activation and subsequent ZG differentiation and demonstrate that PKA activation prevents ZG differentiation through WNT4 repression and WNT pathway inhibition. This suggests that PKA activation in ZF is a key driver of WNT inhibition and lineage conversion. Furthermore, we provide evidence that constitutive PKA activation inhibits, whereas partial inactivation of PKA catalytic activity stimulates β-catenin-induced tumorigenesis. Together, both lower PKA activity and higher WNT pathway activity lead to poorer prognosis in adrenocortical carcinoma (ACC) patients. These observations suggest that PKA acts as a tumour suppressor in the adrenal cortex, through repression of WNT signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / etiology*
  • Animals
  • Carcinogenesis
  • Cell Differentiation
  • Cell Line, Tumor
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Female
  • Humans
  • Mice
  • Phosphorylation
  • Wnt Signaling Pathway*
  • Zona Fasciculata / cytology
  • Zona Fasciculata / metabolism*
  • Zona Glomerulosa / cytology
  • Zona Glomerulosa / metabolism*
  • beta Catenin / metabolism


  • beta Catenin
  • Cyclic AMP-Dependent Protein Kinases