Intracellular trafficking of hormone receptors

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Agonist binding stimulates endocytosis of hormone receptors via vesicular uptake mechanisms. Interactions of the intracellular domains of receptors with specific targeting proteins are crucial for sorting of internalized receptor in endosomes. Some receptors are targeted for very rapid (e.g. β2-adrenergic receptor) or slower (e.g. AT1 angiotensin receptor) recycling pathways, whereas others are targeted to lysosomes for degradation (e.g. EGF receptor or PAR1 protease-activated receptor). This review discusses the mechanisms involved in these processes, which regulate surface receptor expression and set the stage for intracellular signaling of G protein-coupled and growth factor receptors.

Section snippets

Receptor endocytosis

In most cases, endocytosis of hormone receptors is accelerated by agonist binding, whereas nutrient receptors, such as LDL receptor (LDL-R) and transferrin receptor (TfR), are endocytosed constitutively at a rate independent of ligand occupancy 3, 4, 5. The best-identified pathway of receptor endocytosis is mediated by clathrin-coated vesicles (CCVs), first identified as the mechanism of LDL-R endocytosis 4, 5. TfR, EGF receptor (EGFR) and many GPCRs also internalize via CCVs 3, 4, 5. In yeast

Regulation of intracellular trafficking

Segregation of the receptor from its cognate ligand is important during endosomal sorting, as small recycling vesicles have a high surface to volume ratio, which favors the recycling of receptors, whereas dissociated ligands are retained in bulky endosomes [21]. Although this ‘geometric sorting mechanism’ can explain the targeting of dissociated ligands to lysosomes, differences in the recycling pathways and lysosomal targeting of plasma membrane receptors involves specific interactions with

Concluding remarks and future perspectives

Although the major intracellular trafficking pathways of plasma membrane receptors have been mapped, owing to the inherent complexity of the endosomal system, our understanding of these pathways and the signals that target molecules to different pathways is still incomplete. The diversity of intracellular trafficking routes also complicates the identification of the signals responsible for intracellular targeting of the receptors, and more studies are required to elucidate the exact mechanisms

Acknowledgements

This work was supported in part by a Collaborative Research Initiative Grant from the Wellcome Trust (069416/Z/02/Z), and by grants from the Hungarian Ministry of Public Health (ETT 036/2003) and the Hungarian Science Foundation (OTKA T-046445 and OTKA Ts-040865).

References (71)

  • L.A. Volpicelli

    Rab5-dependent trafficking of the m4 muscarinic acetylcholine receptor to the plasma membrane, early endosomes, and multivesicular bodies

    J. Biol. Chem.

    (2001)
  • T. Bremnes

    Regulation and Intracellular Trafficking Pathways of the Endothelin Receptors

    J. Biol. Chem.

    (2000)
  • J.L. Seachrist

    Rab5 association with the angiotensin II type 1A receptor promotes Rab5 GTP binding and vesicular fusion

    J. Biol. Chem.

    (2002)
  • L.B. Dale

    Regulation of angiotensin II type 1A receptor intracellular retention, degradation, and recycling by Rab5, Rab7, and Rab11 GTPases

    J. Biol. Chem.

    (2004)
  • R.H. Oakley

    Association of β-arrestin with G protein-coupled receptors during clathrin-mediated endocytosis dictates the profile of receptor resensitization

    J. Biol. Chem.

    (1999)
  • G. Innamorati

    The long and the short cycle. Alternative intracellular routes for trafficking of G-protein-coupled receptors

    J. Biol. Chem.

    (2001)
  • S. Felder

    Kinase activity controls the sorting of the epidermal growth factor receptor within the multivesicular body

    Cell

    (1990)
  • P. Tsao

    Role of endocytosis in mediating downregulation of G-protein-coupled receptors

    Trends Pharmacol. Sci.

    (2001)
  • P.I. Tsao et al.

    Type-specific sorting of G protein-coupled receptors after endocytosis

    J. Biol. Chem.

    (2000)
  • M.W. McCaffrey

    Rab4 affects both recycling and degradative endosomal trafficking

    FEBS Lett.

    (2001)
  • G.H. Fan

    Differential regulation of CXCR2 trafficking by Rab GTPases

    Blood

    (2003)
  • K. Chaturvedi

    Proteasome involvement in agonist-induced down-regulation of mu and delta opioid receptors

    J. Biol. Chem.

    (2001)
  • U.E. Petaja-Repo

    Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome

    J. Biol. Chem.

    (2001)
  • R. Jockers

    Beta(2)-adrenergic receptor down-regulation. Evidence for a pathway that does not require endocytosis

    J. Biol. Chem.

    (1999)
  • J. Trejo et al.

    The cytoplasmic tails of protease-activated receptor-1 and substance P receptor specify sorting to lysosomes versus recycling

    J. Biol. Chem.

    (1999)
  • R.H. Oakley

    Differential affinities of visual arrestin, beta arrestin1, and beta arrestin2 for G protein-coupled receptors delineate two major classes of receptors

    J. Biol. Chem.

    (2000)
  • A. Claing

    Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and β-arrestin proteins

    Prog. Neurobiol.

    (2002)
  • R.H. Oakley

    Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis

    J. Biol. Chem.

    (2001)
  • L. Hunyady

    Identification of a cytoplasmic Ser-Thr-Leu motif that determines agonist-induced internalization of the AT1 angiotensin receptor

    J. Biol. Chem.

    (1994)
  • M. Tanowitz et al.

    A novel endocytic recycling signal that distinguishes the membrane trafficking of naturally occurring opioid receptors

    J. Biol. Chem.

    (2003)
  • D.F. Guo

    Type I angiotensin II receptor-associated protein ARAP1 binds and recycles the receptor to the plasma membrane

    Biochem. Biophys. Res. Commun.

    (2003)
  • C.M. Vines

    N-formyl peptide receptors internalize but do not recycle in the absence of arrestins

    J. Biol. Chem.

    (2003)
  • A. Marchese et al.

    Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting

    J. Biol. Chem.

    (2001)
  • A. Marchese

    The E3 ubiquitin ligase AIP4 mediates ubiquitination and sorting of the G protein-coupled receptor CXCR4

    Dev. Cell

    (2003)
  • N.P. Martin

    Regulation of V2 vasopressin receptor degradation by agonist-promoted ubiquitination

    J. Biol. Chem.

    (2003)
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