The endocytic catalysts, Rab5a and Rab7, are tandem regulators of thyroid hormone production

Abstract

Rab proteins are small GTPases that control distinct vesicular transport steps. Along the endocytic pathway, Rab5a is a ratelimiting catalyst of internalization, and Rab7 controls trafficking through late endosomes to lysosomes. The dependence of thyroid hormone production by thyrocytes on thyroglobulin endocytosis and intracellular processing in late endosomes͞lysosomes suggests that its rate can be regulated by the expression or function of these endocytic catalysts. We compared the expression level and membrane recruitment of Rab5a and Rab7 in autonomous thyroid adenomas (where the cAMP cascade is constitutively activated) and surrounding quiescent tissues. The concentrations of Rab5a and Rab7, but not of Rab8, were coordinately increased up to 6-fold in adenomas, and correlated with a proportionate decrease in soluble thyroglobulin content (reflecting colloid depletion by accelerated endocytic uptake in hyperactive tissue). In adenomas, a higher proportion of Rab5a and Rab7 was membrane associated, and the equilibrium density of particulate Rab7 and iodine shifted toward lysosomal fractions, indicating that progression along the degradation pathway also was promoted. In cultures of polarized human thyrocytes from normal patients, thyroid-stimulating hormone or forskolin increased, to a similar extent, Rab5a and Rab7 but not Rab8 expression, apical endocytosis of thyroglobulin and lucifer yellow, and basolateral secretion of T 3 and T4. Taken together, these in vivo and in vitro observations demonstrate that thyroid-stimulating hormone, via cAMP, coordinately enhances the expression of Rab5a and Rab7, which promote Tg endocytosis and transfer to lysosomes, respectively, resulting in accelerated thyroid hormone production.

Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information

“…Finally, we found that our ATC/PDTC series had a deregulation of critical genes for thyroid hormone synthesis, such as the overexpression of ARRB2 (b-arrestin 2; Voigt et al, 2000), which is implicated in the desensitization of thyroid-stimulating hormone receptors (TSHR), the underexpression of RAB5A, which participates in the thyroglobulin production (TG; Croizet-Berger et al, 2002), and a diminished expression of TG and PAX8, which has also been observed before in ATC/PDTC series (Onda et al, 2004). Furthermore, the expression of HHEX, a gene related to thyroid morphogenesis and differentiation, was decreased in ATC/PDTC.…”

Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer

“…Rab GTPases regulate tumorigenesis via trafficking-mediated events, and some function in a trafficking-independent manner [22,[37][38][39][40]. Additionally, it is known that several members of the Rab GTPase family affect exosome secretion via the trans-Golgi network or by inducible vesicular trafficking [35,41].…”

Emerging Role of RAB GTPases in Cancer and Human Disease

“…We have shown an increase in RAB25 gene expression in ovarian and breast cancers. Increased RAB25 levels have also been noted in prostate cancer (23), transitional cell carcinoma of the bladder (24), and invasive breast tumor cells (25), suggesting the pathologic role of RAB proteins in the development or progression of tumors in multiple epithelial lineages.…”