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Endocrine and Neuroendocrine Tumors
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Natasha Shrikrishnapalasuriyar, P.N. Plowman, Márta Korbonits, Ashley B. Grossman
RET is a transmembrane receptor protein-tyrosine kinase that is required for the development of the nervous system/neural crest and several other tissues. The mechanism of activation of RET by its glial-cell derived neurotrophic factor (GDNF) ligands requires additional GDNF family receptor-α (GFRα) co-receptors (GFRα1/2/3/4). RET point mutations have been reported in multiple endocrine neoplasia (MEN2A, MEN2B) and medullary thyroid carcinoma. RET fusion proteins have been reported in papillary thyroid and non-small cell lung adenocarcinomas. There has been much recent interest and clinical benefit from the use of the RET inhibitors in the therapy of metastatic medullary thyroid cancer. Vandetanib and cabozantinib have been licensed and are of proven efficacy; recently, a more potent agent, Blue-667, has become available and looks more promising still. This last drug has activity in the brain (of more importance in the RET-driven lung cancers than medullary carcinoma of thyroid). Side-effects such as hypertension, ECG changes, and blood test abnormalities are usually minor but close monitoring is required—as for all cancer patients on tyrosine kinase inhibitors.
Multiple endocrine neoplasia type 2
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
In contrast to other mammalian RTKs, however, RET is unique in that it requires ligand and coreceptor for activation. One of four related ligands, GDNF, NTN, PSP and ART, needs to interact with one of four coreceptors, GFRα-1, 2, 3 and 4 before the heterotetrameric complex can bind RET (Figure 2) (Baloh et al., 1997; Buj-Bello et al., 1997; Davies et al., 1997; Enokido et al., 1998; Jing et al., 1996, 1998; Kotzbauer et al., 1996; Sanicola et al., 1997; Thompson et al., 1998; Treanor et al., 1996; Trupp et al., 1996; Vega et al., 1996). As GFRa family members have no transmembrane domain or cytoplasmic region, they were initially believed not to have direct signaling capabilities until recently, when GDNF treatment of neuronal cell lines not expressing RET resulted in GFRa-1-related Src-like kinase activity (Trupp et al., 1999). Nonetheless, the major role of the GFRa family members in RET activation is to act as adapter molecules. Ligand and GFRa form a complex which then binds to RET and triggers RET dimerization and autophosphorylation as well as phosphorylation of downstream molecules (Baloh et al., 1998). GDNF binds with high affinity to GFRα-1 and to a lesser extent GFRa-2 and with the lowest affinity to GFRα-3 (Figure 2) (Sanicola et al., 1997; Trupp et al., 1998). NTN binds GFRα-2 with high affinity but can also use GFRα-1 as its adaptor (Jing et al., 1998). Thus far, PSP has been shown to bind GFRα-4 only (Enokido et al., 1998; Thompson et al., 1998) although it is currently unclear whether GFRα-4 has a human homolog. ART uses GFRα-3 as its high affinity receptor, and to a lesser extent GFRα-1 (Baloh et al., 1998).
GDF15: a potential therapeutic target for type 1 diabetes
Published in Expert Opinion on Therapeutic Targets, 2022
Soumyadeep Sarkar, John T. Melchior, Hayden R. Henry, Farooq Syed, Raghavendra G. Mirmira, Ernesto S. Nakayasu, Thomas O. Metz
Recently, the interest in GDF15 has spiked due to multiple landmark studies that independently identified the Glial-cell-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL) receptor as the primary receptor for GDF15 [25–28]. GFRAL is primarily expressed in the area postrema (A.P.) and the nucleus of the hindbrain’s solitary tract (NST) neurons. Using GFRAL deficient mice, it has been demonstrated that GDF15 acts on GFRAL in the hindbrain, signaling through AKT, ERK, and PLCy pathways, which reduce appetite and ultimately result in weight loss [25,28]. In addition, it was observed that administration of GDF15 accelerates lipid oxidation and was thought to be secondary to AKT/ERK signaling, which contributes to the observed weight loss phenotype [26,27,29]. Taken together, these studies suggest that GDF15 has a significant impact on pathways critical for energy expenditure. This notion was reinforced by Shuang and colleagues, who demonstrated that GDF15 could specifically regulate lipid metabolism by stimulating hepatic triglyceride secretion via β adrenergic signaling [30]. In addition, multiple studies have demonstrated improved glucose tolerance and insulin sensitivity [31,32]. Whether this improvement is an indirect effect of weight reduction or directly induced by ectopic expression of GDF15 has yet to be determined. Regardless, these studies make GDF15 a highly enticing therapeutic target for treating obesity and other metabolic epidemics currently plaguing the USA [29,33,34].
Differentiation of neonate mouse spermatogonial stem cells on three-dimensional agar/polyvinyl alcohol nanofiber scaffold
Published in Systems Biology in Reproductive Medicine, 2020
Marzieh Ziloochi Kashani, Zohreh Bagher, Hamid Reza Asgari, Mohammad Najafi, Morteza Koruji, Fereshteh Mehraein
To induce the differentiation in mouse SSC differentiation, RA and BMP-4 were added to the cultured cells. The BMP-4 is known to suppress the expression of somatic genes and thus prompts the up-regulation of differentiation genes in the germ cells (Hayashi et al. 2018). In addition, RA is believed to stimulate meiosis mainly through stem cell factor (SCF)/c-Kit signaling pathway (Li et al. 2014). Compared with the pre-differentiation media, the expression levels of Id-4 and Gfrα-1 genes dropped significantly in all culture systems 14 days after the differentiation induction (at the 28th day of the experiment). Id-4 expression reduction was more pronounced in growth factor-stimulated cells, particularly in 3D culture model. In fact, ID-4 mRNA level showed a more than 40-fold reduction in the Dif/3D/+GF system compared to the 3D/+GF system. In comparison, Gfrα-1 expression reduction was more pronounced in growth factor-deprived cells at the end of the culture period. The relative expression of Gfrα-1 was about two-fold higher in Dif/3D/+GF group when compared with Dif/2D/+GF system. Taken together, it seems that SSC differentiation is favored over proliferation when the testicular cells are cultured in the presence of growth factors, particularly in 3D culture medium.
The clinical impact of growth differentiation factor-15 in heart disease: A 2019 update
Published in Critical Reviews in Clinical Laboratory Sciences, 2020
Maria Arkoumani, Nektaria Papadopoulou-Marketou, Nicolas C. Nicolaides, Christina Kanaka-Gantenbein, Nikolaos Tentolouris, Ioannis Papassotiriou
Recently, it was found that GDF-15 binds specifically to glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), which was suggested to be the cognate receptor for GDF-15 responsible for metabolic pathways [10,11]. Thereafter, more trials are focusing on GDF-15 as a potential therapeutic target for obesity [10]. Nowadays, obesity and type 2 diabetes mellitus (T2DM), the most common type of diabetes in adults, are reaching epidemic proportions, even in younger people. T2DM is characterized by hyperglycemia and other significant parameters of the metabolic syndrome, ultimately leading to a higher incidence of CVD and mortality [12]. There is evidence that GDF-15 could also be used as a prognostic biomarker in diabetes and obesity [13]. Recent trials have suggested that GDF-15 is a predictor of early disturbances in glucose tolerance and future occurrence of diabetes in the general population with or without the metabolic syndrome, apart from the prognostic value concerning CV risk and mortality in diabetic patients [14]. GDF-15 has also been investigated as a prognostic biomarker of diabetic nephropathy and the worsening of this major vascular complication of diabetes [15]. Meanwhile, GDF-15, according to recent clinical research, could contribute to preventive and therapeutic strategies in CV morbidity [3]. However, more clinical studies that would investigate the exact pathways of this novel biomarker are certainly needed.