Role of Phosphodiesterases on the Function of Aryl Hydrocarbon Receptor-Interacting Protein (AIP) in the Pituitary Gland and on the Evaluation of AIP Gene Variants.

Familial isolated pituitary adenoma (FIPA) is caused in about 20% of cases by loss-of-function germline mutations in the AIP gene. Patients harboring AIP mutations usually present with somatotropinomas resulting either in gigantism or young-onset acromegaly. AIP encodes for a co-chaperone protein endowed with tumor suppressor properties in somatotroph cells. Among other mechanisms proposed to explain this function, a regulatory effect over the 3',5'-cyclic adenosine monophosphate (cAMP) signaling pathway seems to play a prominent role. In this setting, the well-known interaction between AIP and 2 different isoforms of phosphodiesterases (PDEs), PDE2A3 and PDE4A5, is of particular interest. While the interaction with over-expressed AIP does not seem to affect PDE2A3 function, the reported effect on PDE4A5 is, in contrast, reduced enzymatic activity. In this review, we explore the possible implications of these molecular interactions for the function of somatotroph cells. In particular, we discuss how both PDEs and AIP could act as negative regulators of the cAMP pathway in the pituitary, probably both by shared and independent mechanisms. Moreover, we describe how the evaluation of the AIP-PDE4A5 interaction has proven to be a useful tool for testing AIP mutations, complementing other in silico, in vitro, and in vivo analyses. Improved assessment of the pathogenicity of AIP mutations is indeed paramount to provide adequate guidance for genetic counseling and clinical screening in AIP mutation carriers, which can lead to prospective diagnosis of pituitary adenomas.