Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis

Abstract

The regulatory effect of growth hormone (GH) on its target cells is mediated via the GH receptor (GHR). GH binding to the GHR resultsin the formation of a GH-(GHR) 2 complex and the initiation of signal transduction cascades via the activation of the tyrosine kinase JAK2. Subsequent endocytosis and transport to the lysosome of the ligand-receptor complex is regulated via the ubiquitin system and requires the presence of an intact ubiquitin-dependent endocytosis (UbE) motif in the cytosolic tail of the GHR. Recently, the model of ligand-induced receptor dimerization has been challenged. In this study, ligand-independent GHR dimerization is demonstrated in the endoplasmic reticulum and at the cell surface by coimmunoprecipitation of an epitope-tagged truncated GHR with wild-type GHR. In addition, evidence is provided that the extracellular domain of the GHR is not required to maintain this interaction. Internalization of a chimeric receptor, which fails to dimerize, is independent of an intact UbE-motif. Therefore, we postulate that dimerization of GHR molecules is required for ubiquitin system-dependent endocytosis.

Ubc13 and COOH Terminus of Hsp70-interacting Protein (CHIP) Are Required for Growth Hormone Receptor Endocytosis

“…It is a prototypic member of the class I cytokine receptor family that, after binding to its natural ligand, growth hormone (GH), signals via Janus kinase 2 (Jak2). GH binding to the dimeric GHR induces a rotation in the GHR tail (1,2) that subsequently leads to activation of Jak2 and, ultimately, to activation of signaling cascades via Stat5b, ERK, and MAP kinase pathways (reviewed in Ref. 3).…”

Maximizing the potency of an anti-TLR4 monoclonal antibody by exploiting proximity to Fcγ receptors

“…Alternatively, preformed TLR4 dimers may also exist at the cell surface in an inactive conformation, such as described for other cell membrane receptors including EPOR and GHR, 12,13 which may facilitate antibody co-engagement. In any case, as Hu 15C1 is devoid of any agonistic activity, its Fv domains block TLR4 active dimer conformation necessary to induce receptor signaling.…”

Ensaios para a medida de hormônio do crescimento (GH) e IGF-I: aspectos metodológicos e suas implicações no diagnóstico e seguimento da acromegalia

“…Os domínios para dimerização localizados no receptor do GH não estão dispostos em um formato complementar, em função de existir uma repulsão de cargas elétricas entre eles. Para o sítio 2 de ligação do GH entrar em contato com a segunda molécula do receptor, este necessita realizar um movi- mento de rotação em direção à primeira molécula, resultando na ativação por fosforilação do JAK2 e iní-cio da cascata de transmissão do sinal (12,13).…”

“…Os mé-todos clássicos têm sido a avaliação do grau de supressão do GH após administração oral de glicose (TTOG) juntamente com os níveis séricos de IGF-I (22). Entretanto, após mais de 30 anos da introdução dos imunoensaios para GH, as discrepâncias existentes nos resultados, quando a mesma amostra é dosada por ensaios distintos, podem diferir significativamente (12).…”