ALTERNATIVELY SPLICED FORMS IN THE CYTOPLASMIC DOMAIN OF THE HUMAN GROWTH-HORMONE (GH) RECEPTOR REGULATE ITS ABILITY TO GENERATE A SOLUBLE GH-BINDING PROTEIN

The mechanism underlying the generation of soluble growth hormone bind ing protein (GHBP) probably differs among species, In rats and mice, i t involves an alternatively spliced mRNA, whereas in rabbits, it invol ves limited proteolysis of the membrane-bound growth hormone receptor (GHR). In humans, this latter mechanism is favored, as no transcript c oding for a soluble GHR has been detected so far, To test this hypothe sis, we analyzed COS-7 cells transiently expressing the full-length hu man (h) GHR and observed specific GH-binding activity in the cell supe rnatants. Concomitantly, an alternatively spliced form in the cytoplas mic domain of GHR, hGHR-tr, was isolated from several human tissues, h GHR-tr is identical in sequence to hGHR, except for a 26-bp deletion l eading to a stop codon at position 280, thereby truncating 97.5% of th e intracellular domain of the receptor protein, When compared with hGH R, hGHR-tr showed a significantly increased capacity to generate a sol uble GHBP. Interestingly, this alternative transcript is also expresse d in liver from rabbits, mice, and rats, suggesting that, in these fou r species, proteolysis of the corresponding truncated transmembrane GH R is a common mechanism leading to GHBP generation, These findings sup port the hypothesis that GHBP may at least partly result from alternat ive splicing of the region encoding the intracellular domain and that the absence of a cytoplasmic domain may be involved in increased relea se of GHBP.