Sasaki Nobuya, Hosoda Yayoi, Nagata Aogu, Ding Ming, Cheng Ji-Ming, Miyamoto Tomomi, Okano Shinya, Asano Atsushi, Miyoshi Ichiro, Agui Takashi
Laboratory of Experimental Animal Science, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
Mol Endocrinol. 2007 Jul;21(7):1713-21. doi: 10.1210/me.2007-0040. Epub 2007 Apr 24.
The growth-retarded (grt) mouse has an autosomal recessive, fetal-onset, severe thyroid hypoplasia related to TSH hyporesponsiveness. Through genetic mapping and complementation experiments, we show that grt is a missense mutation of a highly conserved region of the tyrosylprotein sulfotransferase 2 (Tpst2) gene, encoding one of the two Tpst genes implicated in posttranslational tyrosine O-sulfation. We present evidence that the grt mutation leads to a loss of TPST2 activity, and TPST2 isoform has a high degree of substrate preference for TSH receptor (TSHR). The expression of TPST2 can restore TSH-TSHR-mediated cAMP production in fibroblasts derived from grt mice. Therefore, we propose that the tyrosine sulfation of TSHR by TPST2 is crucial for TSH signaling and resultant thyroid gland function.
生长发育迟缓（grt）小鼠患有常染色体隐性、胎儿期发病的严重甲状腺发育不全，这与促甲状腺激素（TSH）反应低下有关。通过基因定位和互补实验，我们发现grt是酪氨酰蛋白硫酸转移酶2（Tpst2）基因高度保守区域的错义突变，该基因编码参与翻译后酪氨酸O-硫酸化的两个Tpst基因之一。我们提供的证据表明，grt突变导致TPST2活性丧失，并且TPST2同工型对促甲状腺激素受体（TSHR）具有高度的底物偏好性。TPST2的表达可以恢复来自grt小鼠的成纤维细胞中TSH-TSHR介导的环磷酸腺苷（cAMP）生成。因此，我们提出TPST2介导的TSHR酪氨酸硫酸化对于TSH信号传导及由此产生的甲状腺功能至关重要。
