Intracellular Trafficking of Epidermal Growth Factor Family Ligands Is Directly Influenced by the pH Sensitivity of the Receptor/Ligand Interaction

French, Anthony R.; Tadaki, Douglas K.; Niyogi, Salil K.; Lauffenburger, Douglas A.

doi:10.1074/jbc.270.9.4334

Cited by 214 publications

(176 citation statements)

References 37 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…There are several examples also where the difference in binding affinity at acidic pH, such as would be present in subcellular compartments, might have a biological significance. The affinity of ligand binding to the epidermal growth factor receptor at acidic pH correlates with the final outcome of endosomal sorting (20). A similar link to biology is seen with major histocompatibility complex interactions with specific peptide ligands (21).…”

Section: Ph and Ionic Strength Modification Of Ccr3 Binding 28208mentioning

confidence: 74%

Chemokine Receptor CCR3 Function Is Highly Dependent on Local pH and Ionic Strength

Dairaghi¹,

Oldham

Bacon³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

The CC chemokine receptor 3 (CCR3) plays an important role in the regulation of the migration of eosinophils, a leukocyte population involved in many inflammatory pathologies including asthma. CCR3 binds to the CC chemokine eotaxin, a promigratory cytokine originally isolated as the key component in a model of eosinophil-induced airway inflammation. We show here that eotaxin/CCR3 binding interactions exhibit a marked sensitivity to relatively small changes in the extracellular environment. In particular, modest variations in the pH and the level of sodium chloride over a range of physiologic and near physiologic conditions had dramatic effects on eotaxin binding and CCR3-mediated cytoplasmic Ca 2؉ mobilization. These biochemical indices were reflected at the functional level as well; small changes in pH and salt also resulted in striking changes in the migration of primary human eosinophils in vitro. These results reveal that relatively small perturbations in extracellular buffer conditions can yield widely disparate interpretations of CCR3 ligand binding and affinities and suggest that modulation of the tissue microenvironment might be utilized to control the affinity and efficacy of chemokine-mediated cell migration.Eosinophils are involved in many inflammatory pathologies including asthma, urticaria, and hypereosinophilic syndrome (1-3). The CC chemokine receptor 3 (CCR3) 1 and its ligands, most notably eotaxin, have been shown to play a central role in controlling eosinophil migration (4 -12). Eotaxin was originally isolated as a protein responsible for eosinophil chemoattraction in the bronchoalveolar fluid of allergen-sensitized guinea pigs (9). Subsequently, the human and mouse homologs were identified and also shown to be chemoattractants for eosinophils (10,12). Eotaxin has been shown to be a primary ligand for the seven-transmembrane G protein-coupled receptor CCR3. The genes for CCR3 and the related receptors CCR1-CCR5 are encoded within a 130-kilobase region of human chromosome 3 (13) indicating recent gene duplication and divergence and perhaps explaining the partial overlap of chemokine ligand repertoires. CCR3 is highly expressed on primary human eosinophils (50,000 -400,000 sites/cell) (5-7), consistent with the potent ability of eotaxin to selectively influence the migration of these cells.The mechanisms by which specific cells are attracted by specific chemokines have been a topic of intense interest and clinical relevance. The question is complicated by the fact that a number of closely related chemokine receptors with overlapping specificities are expressed on many different classes of leukocytes. In addition, the affinity of a specific receptor/ligand interaction can vary depending upon the specific cell type expressing the chemokine receptor, perhaps due to posttranslational modification events or G protein coupling. Thus it appears that cells can modulate their responses to chemokines, but how this is done is not yet clear. While most investigations have focused on factors intrinsic to the...

show abstract

Section: Ph and Ionic Strength Modification Of Ccr3 Binding 28208mentioning

confidence: 74%

Chemokine Receptor CCR3 Function Is Highly Dependent on Local pH and Ionic Strength

Dairaghi¹,

Oldham

Bacon³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Several studies have since examined differences between the effects of EGF and TGF-α on receptor degradation. EGF was shown to be resistant to dissociation from the EGFR in endosomes (French et al, 1995), whilst TGF-α rapidly dissociated from the EGFRs (Ebner and Derynck, 1991) resulting in more efficient targetting of EGFRs to lysosomes with EGF than with TGF-α. This would lead to enhanced biological activity due to repeated presentation of recycled EGFRs at the cell surface, resulting in multiple rounds of signalling.…”

Section: Discussionmentioning

confidence: 99%

Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-α in human prostate cancer cells

et al. 1999

View full text Add to dashboard Cite

SummaryThe epidermal growth factor receptor (EGFR) plays an important role in the development and progression of prostate cancer and its overexpression is associated with decreased survival. With progression, prostate cancer cells switch from epidermal growth factor (EGF) to transforming growth factor α (TGF-α) synthesis, which contributes to autocrine growth and unrestrained proliferation. To define the molecular mechanisms involved in the regulation of EGFR expression by EGF and TGF-α we studied three human prostate cancer cell lines, androgen-responsive (LNCaP) and -unresponsive (DU145 and PC3). Here we show that TGF-α stabilized EGFR mRNA two-to threefold in all three cell lines, whilst EGF stabilized EGFR mRNA ~ twofold in LNCaP and DU145 cells, but not in PC3 cells. Both ligands increased EGFR transcription in LNCaP and DU145 cells, with less effect in PC3 cells. In all three cell lines EGF reduced total EGFR protein levels more than TGF-α, but this was associated with a greater increase in de novo protein synthesis with EGF compared to TGF-α. Only EGF, however, shortened EGFR protein stability (half-life decreased from 5 h to 120 min), resulting in rapid disappearance of newly synthesized EGFR protein. Both ligands increased total LNCaP and DU145 cell numbers. These studies demonstrate that the EGF-and TGF-α-induced upregulation of EGFR mRNA and protein in human prostate cancer cell lines is complex and occurs at multiple, transcriptional and post-transcriptional levels. Taken together, these data provide novel insight into the molecular mechanisms by which TGF-α would preferentially maintain an autocrine loop in human prostate cancer cells. Furthermore, this work suggests that in human prostate cancer cells ligand-specific differential intracellular trafficking of the EGFR plays a major role in regulating its expression.

show abstract

“…For instance, the association of TGF-α with EGFR is disrupted at endosomal pH allowing for recycling of ligand-free receptors. EGF, however, has a higher affinity for EGFR at endosomal pH and the EGF-EGFR complex would be more likely to be targeted for lysosomal destruction [61, 93,94].…”

Section: Signal Attenuationmentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

647

503

View full text Add to dashboard Cite

The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.

show abstract

Intracellular Trafficking of Epidermal Growth Factor Family Ligands Is Directly Influenced by the pH Sensitivity of the Receptor/Ligand Interaction

Cited by 214 publications

References 37 publications

Chemokine Receptor CCR3 Function Is Highly Dependent on Local pH and Ionic Strength

Chemokine Receptor CCR3 Function Is Highly Dependent on Local pH and Ionic Strength

Complex post-transcriptional regulation of EGF-receptor expression by EGF and TGF-α in human prostate cancer cells

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Contact Info

Product

Resources

About