Sci. STKE, 30 July 2002
Receptors Preassociated Receptors
The evidence for ligand-independent preassociated transmembrane-type receptors continues to grow. Gent et al. report that when overexpressed in cultured cells, the receptor for growth hormone (GH) dimerizes in the absence of ligand in both its glycosylated precursor state in the endoplasmic reticulum and in its mature form at the plasma membrane. Addition of GH did not alter dimer formation, as determined by immunoprecipitation. Removal of the receptor extracellular domain by proteinase K-meditated digestion did not prevent heterodimer formation, indicating that the remainder of the protein was critical for subunit interaction. However, in contrast to GH receptor, a chimeric receptor, in which the GH receptor extracellular domain was replaced by that of the low-density lipoprotein receptor, failed to dimerize. The authors speculate that the extracellular domain may be required in the receptor assembly process in the ER but not in maintaining the association at the plasma membrane. Ligand binding may cause a conformation change that initiates a signaling cascade.
Such preformed ligand-independent receptors have been suspected for the epidermal growth factor (EGF) receptor, but the potential influence of endogenous ligand remained in question. Yu et al. resolve the issue by overexpressing human EGF receptor in a mouse cell line that does not express any EGF receptor family members and, presumably, no activating ligand. In the absence of EGF, overexpressed EGF receptor was detected by cross-linking and by immunoprecipitation. However, in the absence of ligand, the dimers were not highly phosphorylated, nor were some downstream receptor substrates, indicating that the ligand-independent preformed dimers were not active. When the EGF receptor cytoplasmic domain was replaced with that of the erythropoietin receptor, dimers were only observed in the presence of ligand, indicating that the cytoplasmic region is critical for dimer formation. It is thought the preassociation could expedite receptor activation upon ligand binding.
X. Yu, K. D. Sharma, T. Takahashi, R. Iwamoto, E. Mekada, Ligand-independent dimer formation of epidermal growth factor receptor (EGFR) is a step separable from ligand-induced EGFR signaling. Mol. Biol. Cell 13, 2547-2557 (2002). [Abstract] [Full Text]
J. Gent, P. van Kerkhof, M. Roza, G. Bu, G. J. Strous, Ligand-independent growth hormone receptor dimerization occurs in the endoplasmic reticulum and is required for ubiquitin system-dependent endocytosis. Proc. Natl. Acad. Sci. U.S.A. 99, 9858-9863 (2002). [Abstract] [Full Text]
Citation: Preassociated Receptors. Sci. STKE 2002, tw279 (2002).
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