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The anti-Müllerian hormone type II (AMHRII) receptor is the primary receptor for anti-Müllerian hormone (AMH), a protein produced by Sertoli cells and responsible for the regression of the Müllerian duct in males. AMHRII is a membrane protein containing an N-terminal extracellular domain (ECD) that binds AMH, a transmembrane domain, and an intracellular domain with serine/threonine kinase activity. Mutations in the AMHRII gene lead to persistent Müllerian duct syndrome in human males. In this paper, we have investigated the effects of 10 AMHRII mutations, namely 4 mutations in the ECD and 6 in the intracellular domain. Molecular models of the extra- and intracellular domains are presented and provide insight into how the structure and function of eight of the mutant receptors, which are still expressed at the cell surface, are affected by their mutations. Interestingly, two soluble receptors truncated upstream of the transmembrane domain are not secreted, unless the transforming growth factor beta type II receptor signal sequence is substituted for the endogenous one. This shows that the AMHRII signal sequence is defective and suggests that AMHRII uses its transmembrane domain instead of its signal sequence to translocate to the endoplasmic reticulum, a characteristic of type III membrane proteins.

SUMMARY:Glioma and renal cell carcinoma (RCC) cells express high affinity interleukin 13 (IL13) binding sites, but only RCC cell proliferation was inhibited by IL13. Both of these two cell types are IL2-receptor ␥c chain-negative. We thus used these cell models to investigate the patterns of expression of IL13R␣1, IL13R␣2, and IL4R␣ chains and the role of IL13R␣2 in the response to IL13. Using new specific antibodies and flow cytometry, we observed a similar surface expression of IL4R␣ and IL13R␣1 chains in most RCC and glioma cells, whereas IL13R␣2 was only present on five of six glioma cell lines. In all glioma cell lines, the amount of IL13R␣2 expression was 10 to 30 times higher than that of the two other chains. Although there was no surface or intracellular expression of IL13R␣2, its mRNA was detected in three of seven RCC cell lines. The expression on RCC cells of IL13R␣2 mRNA and/or that of high-affinity IL13 binding sites is not sufficient to predict IL13R␣2 protein expression. Blocking experiments showed that IL4 and IL13 strongly inhibited RCC cell proliferation through a unique receptor composed of IL4R␣ and IL13R␣1 chains. Using RCC cells stably transfected with IL13R␣2 cDNA, we showed that the overexpression of IL13R␣2 decreased the response to IL13 but not that to IL4. Our results demonstrate that IL13R␣2 acts as a decoy receptor for IL13 and that it may exert a tight regulation of IL13 activity without impairing the IL4 response of the same cell target. (Lab Invest 2001, 81:1223-1231.