Endocrine Abstracts (2002) 4 S22

TRUNCATED CYTOKINE RECEPTORS AND GH ANTAGONISTS: SIGNALLING AND TRAFFICKING

M Maamra


Clinical Sciences, Sheffield University, UK.


Common features for cytokine receptors are the presence of truncated receptors and production of soluble receptor. mRNAs encoding truncated growth hormone and leptin receptors (GHR and ObR) have been detected. The truncated GHR1-279 has a dominant negative action on the full-length receptor (GHRfl). GH is internalised very rapidly by cells expressing GHRfl. In contrast, the GHR1-279 showed delayed and reduced internalisation of GH. This could explain its dominant negative action on GHRfl and the increase in GHBP levels observed in patients heterozygous for mutations generating truncated GHRs. We provide evidence that Jak-Stat signalling is not essential for GHR internalisation. The GH antagonist, B2036, can inhibit GH activation of the Jak-Stat pathway but is internalised by cells expressing GHRfl. The pegylated form of B2036 (pegvisomant) is currently being successfully used as a treatment for acromegaly. Pegylation greatly reduces the affinity for GHRfl compared to GH and B2036, whereas its affinity for the soluble receptor is unchanged compared to GH. These results provide an explanation for the high dose requirement for Pegvisomant and the observation of high GHBP levels in patients treated with this drug. The leptin receptor is present in human tissues as a long isoform, ObRb, and a truncated receptor expressed ubiquitously, ObRa. We show that ObRb is capable of signalling through Stats and Erks, whereas ObRa signals only via the Erks. ObRb signalling via Stats is relatively resistant to dominant negative repression by ObRa. ObRa is expressed at the cell surface at higher levels than ObRb and generates greater levels of soluble receptor LBP. As with GHBP a metalloprotease could be the LBP generating enzyme and ObRa could act as a source of LBP for the mediated transport of leptin to its central sites of action. In conclusion truncated cytokine receptors regulate signalling and generation of soluble receptors.

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