scholarly journals Role of receptor tyrosine kinases in G-protein-coupled receptor regulation of Ras: transactivation or parallel pathways?

2003 ◽  
Vol 376 (1) ◽  
pp. e9-e10 ◽  
Author(s):  
Julian DOWNWARD
Keyword(s):  
G Protein ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Nucleotide Exchange ◽  
Lpa Receptor ◽  
Ras Protein ◽  
Ras Activation ◽  
Epidermal Growth ◽  
G Protein Coupled

Ras protein regulation by G-protein-coupled receptors has been thought to occur through transactivation of receptor tyrosine kinases. New evidence suggests that these two receptor types independently control different pathways leading to Ras activation in response to lysophosphatidic acid (LPA). Epidermal growth factor receptor function is needed for basal nucleotide exchange on Ras, whereas the LPA receptor controls an inducible exchange activity.

scholarly journals Ligand bias in receptor tyrosine kinase signaling

2020 ◽  
Vol 295 (52) ◽  
pp. 18494-18507
Author(s):  
Kelly Karl ◽  
Michael D. Paul ◽  
Elena B. Pasquale ◽  
Kalina Hristova
Keyword(s):  
G Protein ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
G Protein Coupled Receptors ◽  
Operational Model ◽  
Tyrosine Kinase Signaling ◽  
Rtk Signaling ◽  
Ligand Bias ◽  
G Protein Coupled

Ligand bias is the ability of ligands to differentially activate certain receptor signaling responses compared with others. It reflects differences in the responses of a receptor to specific ligands and has implications for the development of highly specific therapeutics. Whereas ligand bias has been studied primarily for G protein–coupled receptors (GPCRs), there are also reports of ligand bias for receptor tyrosine kinases (RTKs). However, the understanding of RTK ligand bias is lagging behind the knowledge of GPCR ligand bias. In this review, we highlight how protocols that were developed to study GPCR signaling can be used to identify and quantify RTK ligand bias. We also introduce an operational model that can provide insights into the biophysical basis of RTK activation and ligand bias. Finally, we discuss possible mechanisms underpinning RTK ligand bias. Thus, this review serves as a primer for researchers interested in investigating ligand bias in RTK signaling.

scholarly journals Quantifying the strength of heterointeractions among receptor tyrosine kinases from different subfamilies: Implications for cell signaling

2020 ◽  
Vol 295 (29) ◽  
pp. 9917-9933 ◽  
Author(s):  
Michael D. Paul ◽  
Hana N. Grubb ◽  
Kalina Hristova
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Eph Receptor ◽  
Vital Cell ◽  
Cell Processes ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that control vital cell processes such as cell growth, survival, and differentiation. There is a growing body of evidence that RTKs from different subfamilies can interact and that these diverse interactions can have important biological consequences. However, these heterointeractions are often ignored, and their strengths are unknown. In this work, we studied the heterointeractions of nine RTK pairs, epidermal growth factor receptor (EGFR)–EPH receptor A2 (EPHA2), EGFR–vascular endothelial growth factor receptor 2 (VEGFR2), EPHA2–VEGFR2, EPHA2–fibroblast growth factor receptor 1 (FGFR1), EPHA2–FGFR2, EPHA2–FGFR3, VEGFR2–FGFR1, VEGFR2–FGFR2, and VEGFR2–FGFR3, using a FRET-based method. Surprisingly, we found that RTK heterodimerization and homodimerization strengths can be similar, underscoring the significance of RTK heterointeractions in signaling. We discuss how these heterointeractions can contribute to the complexity of RTK signal transduction, and we highlight the utility of quantitative FRET for probing multiple interactions in the plasma membrane.

scholarly journals The Ubiquitin-like Protein PLIC-2 Is a Negative Regulator of G Protein-coupled Receptor Endocytosis

2008 ◽  
Vol 19 (3) ◽  
pp. 1252-1260 ◽  
Author(s):  
Elsa-Noah N'Diaye ◽  
Aylin C. Hanyaloglu ◽  
Kimberly K. Kajihara ◽  
Manojkumar A. Puthenveedu ◽  
Ping Wu ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
G Protein ◽  
Growth Factor Receptor ◽  
Negative Regulator ◽  
Regulatory Function ◽  
Receptor Endocytosis ◽  
Epidermal Growth ◽  
G Protein Coupled

The activity of many signaling receptors is regulated by their endocytosis via clathrin-coated pits (CCPs). For G protein-coupled receptors (GPCRs), recruitment of the adaptor protein arrestin to activated receptors is thought to be sufficient to drive GPCR clustering in CCPs and subsequent endocytosis. We have identified an unprecedented role for the ubiquitin-like protein PLIC-2 as a negative regulator of GPCR endocytosis. Protein Linking IAP to Cytoskeleton (PLIC)-2 overexpression delayed ligand-induced endocytosis of two GPCRs: the V2 vasopressin receptor and β-2 adrenergic receptor, without affecting endocytosis of the transferrin or epidermal growth factor receptor. The closely related isoform PLIC-1 did not affect receptor endocytosis. PLIC-2 specifically inhibited GPCR concentration in CCPs, without affecting membrane recruitment of arrestin-3 to activated receptors or its cellular levels. Depletion of cellular PLIC-2 accelerated GPCR endocytosis, confirming its regulatory function at endogenous levels. The ubiquitin-like domain of PLIC-2, a ligand for ubiquitin-interacting motifs (UIMs), was required for endocytic inhibition. Interestingly, the UIM-containing endocytic adaptors epidermal growth factor receptor protein substrate 15 and Epsin exhibited preferential binding to PLIC-2 over PLIC-1. This differential interaction may underlie PLIC-2 specific effect on GPCR endocytosis. Identification of a negative regulator of GPCR clustering reveals a new function of ubiquitin-like proteins and highlights a cellular requirement for exquisite regulation of receptor dynamics.

Conformational Analysis of the Phosphorylated Epidermal Growth Factor Receptor

1999 ◽  
Vol 19 (5) ◽  
pp. 397-402 ◽  
Author(s):  
Anupam Bishayee ◽  
Laura Beguinot ◽  
Subal Bishayee
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Conformational Changes ◽  
Tyrosine Kinases ◽  
Egf Receptor ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Tyrosine Residue ◽  
Peptide Antibody ◽  
Epidermal Growth

Phosphorylation-induced conformational changes have been well documented with different receptor tyrosine kinases. However, the susceptible epitopes and the tyrosine residue(s) involved in particular structural alteration mostly remain to be determined. Using a conformation-specific anti-peptide antibody, we have not only identified one such domain in the C-terminal tail of the EGF receptor but also identified the phosphate acceptor sites that are involved in the conformational change.

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