Survival of colorectal cancer patients is strongly dependent on development of distant metastases. S100A4 is a prognostic biomarker and inducer for colorectal cancer metastasis. Besides exerting intracellular functions, S100A4 is secreted extracellularly. The receptor for advanced glycation end products (RAGE) is one of its interaction partners. The impact of the S100A4-RAGE interaction for cell motility and metastasis formation in colorectal cancer has not been elucidated so far. Here we demonstrate the RAGE-dependent increase in migratory and invasive capabilities of colorectal cancer cells via binding to extracellular S100A4. We show the direct interaction of S100A4 and RAGE, leading to hyperactivated MAPK/ERK and hypoxia signaling. The S100A4-RAGE axis increased cell migration (P<0.005) and invasion (P<0.005), which was counteracted with recombinant soluble RAGE and RAGE-specific antibodies. In colorectal cancer patients, not distantly metastasized at surgery, high RAGE expression in primary tumors correlated with metachronous metastasis, reduced overall (P=0.022) and metastasis-free survival (P=0.021).In summary, interaction of S100A4-RAGE mediates S100A4-induced colorectal cancer cell motility. RAGE by itself represents a biomarker for prognosis of colorectal cancer. Thus, therapeutic approaches targeting RAGE or intervening in S100A4-RAGE-dependent signaling early in tumor progression might represent alternative strategies restricting S100A4-induced colorectal cancer metastasis.

The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.

No abstract

The thyrotropin receptor (TSHR), the lutropin- (LHR), and the follicotropin receptor (FSHR) belong to glycoprotein hormone receptors (GPHR), a subgroup of the class A G-protein coupled receptors. In this review, the unique features of GPHR have been taken into account for their pharmacological interventions: i) The respective hormone and stimulating or blocking antibodies are binding on the large ectodomain that is ii) via a hinge region, containing iii) an internal tethered agonist linked to the transmembrane domain. iv) Multimerization and mechanisms for negative or positive cooperativity of GPHR upon ligand binding and v) dimer- and oligomeric arrangements enabling trans-activation on GPHR signaling are considered. Available knowledge concerning the modulation of the GPHR (mal)-function and associated structural aspects by diverse entities such as antibodies, chaperones, peptides, small molecule agonists, inverse agonists, and antagonists is summarized. The TSHR is important with respect to autoimmune [Graves’ disease (GD), Graves’ orbitopathy (GO)] or non-autoimmune thyroid dysfunctions and cancer-development. To date there is neither an agonist nor antagonist modulator of pathogenic such as TSHR signaling in the clinics. However, several different ligands monoclonal stimulating and inhibiting antibodies and small molecule drug-like ligands have been reported in the last decade. In special focus are the most recent findings regarding the development and use of small molecule TSHR ligands. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts towards understanding the interplay of TSHR multimers, especially their interaction with drug-like ligands. Important in this context is the biased ligand development.