RT Dissertation/Thesis
T1 Fundamental structural and biochemical features for the obestatin/GPR39 system mitogenic action
A1 Otero Alén, Begoña
K1 Obestatin
K1 GRP39
K1 Gastric cancer
AB In 2005, a new peptide derived from the ghrelin peptide precursor, named obestatin, was discovered. One of the most important functions of obestatin is its mitogenic activity. Obestatin and the GPR39 receptor were reported to be involved in the control of mitogenesis of gastric cancer cell lines; this fact prompted us to investigate obestatin/GPR39 signalling and the relationship between the system and gastric cancer progression, and explored their potential functional roles.The main objective of this doctoral thesis is to establish the relationship between obestatin and GPR39 receptor in healthy and tumour-like surroundings, from structural to tissue level, to determinate the fundamental parameters of its mitogenic bioactivity. This issue will be accomplished with the following points:1. To determine the structural features of obestatin required for the interaction with its receptor.2. To elucidate the detailed activation/regulation mechanism of GPR39 receptor signalling triggered by obestatin.3. To analyse the role of obestatin/GPR39 system in the development and malignity of tumours.Our results demonstrated that:At structural level, the amidation at the C-terminus is essential to adopt an α-helix structure and stabilize the GPR39 conformations necessary for the full range of receptor activities. Furthermore, human (11-23)-obestatin is able to induce selective coupling to the β-arrestin-dependent signalling, representing the first example of an endogenous biased ligand for GPR39. Meanwhile, mouse and human obestatin exhibit clear conformational differences beyond their primary structure. This evidence supports the species-specific activity of this peptide. Additionally, obestatin-GPR39 interaction might involve an E/Z isomerization of the peptide and the posibility that GPR39 could be acting as a prolyl cis-trans isomerase.Regarding the activation/regulation mechanism of GPR39 signalling triggered by obestatin, our results show that obestatin increases GPR39 phosphorylation and induces receptor endocytosis. In this signalling network, the transactivation process induced by obestatin GPR39-EGFR is a key mechanism, regulated by MMPs. The RTKs and proteases expression profiles confirm the implication of EGFR and MMPs in the obestatin signalling pathway, and introduce other proteases and RTKs in this cross-talk.In human tissues, we observe that the obestatin/GPR39 system regulates pepsinogen secretion. This result provide the first biological function for the obestatin/GPR39 system in healthy stomach. This system also regulates proliferation, motility, EMT, and invasion of gastric cancer cells. More importantly, the GPR39 expression levels found in human gastric adenocarcinomas provide the rationale for including GPR39 as a prognostic marker of these tumours. The ubiquitous expression of GPR39 and its cancer-associated overexpression, together with obestatin, provokes the proliferation and cell motillity of diverse human cancer cell lines. Moreover, these effects depend not only on GPR39, but also on the expression of key components of its signalling pathway, i.e. RTKs, proteases.
YR 2016
FD 2016
LK http://hdl.handle.net/10347/14993
UL http://hdl.handle.net/10347/14993
LA eng
DS Minerva
RD 24 abr 2026