RET signalling in the pituitary: a double-edged sword for differentiation, apoptosis and therapeutic strategies in acromegaly

The discovery of RET mutations in multiple endocrine neoplasia type 2A (MEN2A) in 1993 ignited a revolution in our understanding of this versatile receptor. Since then, the influence of RET has expanded to encompass diverse organs, including the pituitary gland. This review explores the multifaceted role of RET in somatotrophs, focusing on two opposing pathways: proliferation versus differentiation and apoptosis. The binding of glial-derived neurotrophic factor (GDNF) to RET promotes pituitary cell survival and inhibits PIT1-dependent differentiation, while low levels of GDNF trigger differentiation via PIT1. Excessive PIT1, on the other hand, will lead to apoptosis through caspase-3 activation involving the adaptor protein AIP and CDKN2A-ARF/p53. Pathogenic mutations in AIP can disrupt this apoptotic pathway, contributing to somatotrophinoma or prolactinoma development. In this concise review, we highlight the potential of CDKN2A-ARF expression as a prognostic marker for therapy response and discuss the promise of novel RET tyrosine kinase inhibitors for aggressive somatotrophinomas.