RET signalling provides tumorigenic mechanism and tissue specificity for AIP-related somatotrophinomas

Abstract

It is unclear how loss-of-function germline mutations in the widely-expressed co-chaperone AIP, result in young-onset growth hormone secreting pituitary tumours. The RET receptor, uniquely co-expressed in somatotrophs with PIT1, induces apoptosis when unliganded, while RET supports cell survival when it is bound to its ligand. We demonstrate that at the plasma membrane, AIP is required to form a complex with monomeric-intracellular-RET, caspase-3 and PKCδ resulting in PIT1/CDKN2A-ARF/p53-apoptosis pathway activation. AIP-deficiency blocks RET/caspase-3/PKCδ activation preventing PIT1 accumulation and apoptosis. The presence or lack of the inhibitory effect on RET-induced apoptosis separated pathogenic AIP variants from non-pathogenic ones. We used virogenomics in neonatal rats to demonstrate the effect of mutant AIP protein on the RET apoptotic pathway in vivo. In adult male rats altered AIP induces elevated IGF-1 and gigantism, with pituitary hyperplasia through blocking the RET-apoptotic pathway. In females, pituitary hyperplasia is induced but IGF-1 rise and gigantism are blunted by puberty. Somatotroph adenomas from pituitary-specific Aip-knockout mice overexpress the RET-ligand GDNF, therefore, upregulating the survival pathway. Somatotroph adenomas from patients with or without AIP mutation abundantly express GDNF, but AIP-mutated tissues have less CDKN2A-ARF expression. Our findings explain the tissue-specific mechanism of AIP-induced somatotrophinomas and provide a previously unknown tumorigenic mechanism, opening treatment avenues for AIP-related tumours.

Molecular genetic testing in the management of pituitary disease

“…At the plasma membrane, AIP plays an essential role in the initial steps of the RET‐apoptotic pathway in PIT1 expressing cells. Lack of AIP or pathogenic mutations block this pathway promoting the RET‐survival pathway characteristic of the pituitary tumours 35 . This mechanism can also explain the unique tissue and cell‐type specificity of AIP ‐related tumours, as PIT1 and RET together are typically only expressed in somato‐ and lactotroph cells.…”

“…Lack of AIP or pathogenic mutations block this pathway promoting the RETsurvival pathway characteristic of the pituitary tumours. 35 This mechanism can also explain the unique tissue and cell-type specificity of AIPrelated tumours, as PIT1 and RET together are typically only expressed in somato-and lactotroph cells. In AIP-mutation positive tumours microRNA-34a (miR-34a) was found to be upregulated, where it correlates with pro-oncogenic features, high cAMP levels, and impaired response to first-generation somatostatin analogues.…”

Molecular targets in acromegaly

“…CDK and their inhibitors may serve as markers of somatotroph adenoma subtypes ( 4 , 79 ). p21, a CDK inhibitor that plays a key role in cell senescence, is activated to maintain the benign nature of somatotroph adenomas ( 45 , 71 ).…”

AIP: A double agent? The tissue-specific role of AIP as a tumour suppressor or as an oncogene

“…Several tumorigenic mechanisms have been suggested, including stimulation of the tumour suppressor ZAC [6] or the inhibitory G protein Gα i2 [7]. More recently, an exciting mechanism has been put forward which explains not just the tumorigenic effect of AIP deficiency but also the tissue-specific nature of the tumorigenesis [8]: AIP supports the dependence receptor function of RET. AIP is part of a complex with monomericintracellular-RET, caspase-3 and PKCδ resulting in a balanced PIT1/ CDKN2A-ARF/p53-pathway-induced apoptosis.…”