Caveolar internalization of growth hormone.

Caveolae are plasma membrane specializations formed by caveolin and characterized by their dependence on membrane cholesterol for structural integrity. We have investigated the role of caveolae in the internalization of GH in CHO cells stably transfected with GH receptor cDNA (CHO-GHR1-638). We show by immunogold electron microscopy that a portion of the GH receptor at the cell surface is localized to or near caveolin-containing structures and upon GH stimulation the receptor aggregates in caveolae. Similarly the hormone is observed to be aggregated in caveolae and a portion of the hormone is internalized into the cell in caveolin-containing vesicles. Disruption of caveolar integrity by sterol-binding agents (filipin, nystatin) partially inhibits internalization of 125I-hGH whereas internalization of hormone is not affected by non-sterol-binding agents which also insert into the cell membrane (polymyxin B, xylazine). Transient transfection of caveolin cDNA into CHO cells concomitantly transfected with GH receptor cDNA increases both the internalization of hormone and the GH stimulation of STAT-mediated transcription. In conclusion, we demonstrate that caveolae constitute one pathway for the internalization of GH. Such an internalization pathway may also be utilized by other members of the cytokine receptor superfamily.

[Growth hormone receptor]. / Le récepteur de l'hormone de croissance.

Growth hormone (GH) exerts multiple actions and GH receptors have been demonstrated in a variety of tissues. Changes in the number of hepatic GH receptors have been demonstrated in several models of growth failure in rats. Cloning of the rabbit and human liver GH receptor has shown that the receptor is a single polypeptide chain of 620 amino acids, made of an extracellular hormone-binding domain, with 7 cysteines and 5 potential glycosylation sites, a unique transmembrane domain and a long cytoplasmic domain. The GH receptor belongs to a new family including prolactin and cytokine receptors. Signal transduction pathways are unknown for these receptors, which do not possess any consensus sequences homologous to tyrosine kinases. The GH-binding protein (GH-BP), identified in plasma of man and other species, corresponds to the extracellular binding domain of the membrane GH receptor. Evaluation of the GH-BP is a direct approach to the GH receptor in man in vivo. Complete absence of GH binding activity has been found in the plasma of patients with Laron dwarfism, in particular those for whom a mutation in the GH receptor gene has been demonstrated.

[The molecular bases of the pathogenesis of AIDS]. / Molekuliarnye osnovy patogeneza SPID.

The comparative study of the amino acid sequence of gp120 in human immunodeficiency virus (HIV) strains HTLV-III and ARV-2 and the amino end areas of the growth hormone receptors of human skin and the insulin receptors has been carried out, thus making it possible to predict the existence of two compact domains connected with an area of a peptide chain. This area is incapable of the formation of a compact globular structure due to a high content of the remnants of proline. The data obtained as the result of electron microscopic study in combination with image processing have confirmed the predicted three-dimensional structure of gp120. This study has also shown that the amino acid sequence of some regions in the domains of gp120 has a significant degree of homology with similarly located regions of the growth hormone and insulin receptors; in its turn, this amino acid sequence is homologous to the framework regions of the VH domain of immunoglobulin. Antibodies to this VH domain specifically react with recombinant HTLV-III antigen. On the basis of the data obtained in our experiments and from the analysis clinico-immunological information, we have come to the conclusion that AIDS is an autoimmune disease induced by HIV due to the structural homology of gp120 with highly important receptors of human cells.

Identification of a cDNA encoding a long form of prolactin receptor in human hepatoma and breast cancer cells.

Human PRL receptor cDNA clones from hepatoma (Hep G2) and breast cancer (T-47D) libraries were isolated by using a rat PRL receptor cDNA probe. The nucleotide sequence predicts a mature protein of 598 amino acids with a much longer cytoplasmic domain than the rat liver PRL receptor. Although this extended region has additional segments of localized sequence identity with the human GH receptor, there is no identity with any consensus sequences known to be involved in hormonal signal transduction. This cDNA will be a valuable tool to better understand the role of PRL in the development and growth of human breast cancer.