Sortilin Is a Putative Postendocytic Receptor of Thyroglobulin

Abstract

The Vps10p family member sortilin is involved in various cell processes, including protein trafficking. Here we found that sortilin is expressed in thyroid epithelial cells (thyrocytes) in a TSH-dependent manner, that the hormone precursor thyroglobulin (Tg) is a high-affinity sortilin ligand, and that binding to sortilin occurs after Tg endocytosis, resulting in Tg recycling. Sortilin was found to be expressed intracellularly in thyrocytes, as observed in mouse, human, and rat thyroid as well as in FRTL-5 cells. Sortilin expression was demonstrated to be TSH dependent, both in FRTL-5 cells and in mice treated with methimazole and perchlorate. Plasmon resonance binding assays showed that Tg binds to sortilin in a concentration-dependent manner and with high affinity, with Kd values that paralleled the hormone content of Tg. In addition, we found that Tg and sortilin interact in vivo and in cultured cells, as observed by immunoprecipitation, in mouse thyroid extracts and in COS-7 cells transiently cotransfected with sortilin and Tg. After incubation of FRTL-5 cells with exogenous, labeled Tg, sortilin and Tg interacted intracellularly, presumably within the endocytic pathway, as observed by immunofluorescence and immunoelectron microscopy, the latter technique showing some degree of Tg recycling. This was confirmed in FRTL-5 cells in which Tg recycling was reduced by silencing of the sortilin gene and in CHO cells transfected with sortilin in which recycling was increased. Our findings provide a novel pathway of Tg trafficking and a novel function of sortilin in the thyroid gland, the functional impact of which remains to be established.

ProNGF is a potential diagnostic biomarker for thyroid cancer

“…In thyroid cancer, TrkA expression and gene rearrangements have been reported [ 21 , 14 , 15 , 30 ] and given the tyrosine kinase activity of TrkA, it participates in the deregulation of thyroid cancer cell growth [ 16 , 17 ]. It has also been shown that p75 NTR is widely expressed in papillary thyroid carcinoma [ 18 ] and sortilin is expressed in thyroid epithelial cells, where it contributes to the recycling of the thyroid hormone precursor thyroglobulin [ 31 ]. However, the determination of a biological activity for proNGF has not been investigated here.…”

The Vps10p-domain receptor family

“…Thyroglobulin was identified as a ligand of Sortilin [55]. Thyroglobulin, the thyroid hormone precursor, is synthesized by thyroid epithelial cells (thyrocytes) and secreted into the lumen of thyroid follicles, where it undergoes hormone formation [56].…”

“…It is well established that Megalin, a member of the LDL receptor family, mediates thyroglobulin uptake and transcytosis [57]. A recent study demonstrates that Sortilin is expressed in thyrocytes in a thyroid-stimulating hormone (TSH)-dependent manner and that it interacts with thyroglobulin in postendocytic endosomes and partakes in thyroglobulin recycling [55]. Recycling of internalized ligands may be a general function of Sortilin in addition to internalization and Golgi-toendosome sorting.…”

Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion

“…In non-neuronal tissues, sortilin expression has been reported in skeletal and heart muscles, adrenal gland, thyroid, lymphocyte B cells as well as keratinocytes and adipocytes [ 9 – 12 ]. A few cancer cell lines have been shown to express sortilin and are impacted by its disruption.…”