scholarly journals A perspective on structural and mechanistic aspects of protein O-fucosylation

2018 ◽  
Vol 74 (8) ◽  
pp. 443-450 ◽  
Author(s):  
Erandi Lira-Navarrete ◽  
Ramon Hurtado-Guerrero
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Structural Information ◽  
Type I ◽  
Post Translational Modification ◽  
Protein Substrates ◽  
The Past ◽  
Epidermal Growth ◽  
Catalytic Mechanisms

Protein O-fucosylation is an important post-translational modification (PTM) found in cysteine-rich repeats in proteins. Protein O-fucosyltransferases 1 and 2 (PoFUT1 and PoFUT2) are the enzymes responsible for this PTM and selectively glycosylate specific residues in epidermal growth factor-like (EGF) repeats and thrombospondin type I repeats (TSRs), respectively. Within the past six years, crystal structures of both enzymes have been reported, revealing important information on how they recognize protein substrates and achieve catalysis. Here, the structural information available today is summarized and how PoFUT1 and PoFUT2 employ different catalytic mechanisms is discussed.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

Selective Inhibition of Type I Collagen Synthesis in Osteoblastic Cells by Epidermal Growth Factor*

Endocrinology ◽  
1984 ◽  
Vol 115 (3) ◽  
pp. 867-876 ◽  
Author(s):  
RYU-ICHIRO HATA ◽  
HISAE HORI ◽  
YUTAKA NAGAI ◽  
SHIGEYASU TANAKA ◽  
MAYURI KONDO ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Collagen Synthesis ◽  
Type I Collagen ◽  
Selective Inhibition ◽  
Osteoblastic Cells ◽  
Type I ◽  
Epidermal Growth

Factor inhibiting hypoxia-inducible factor (FIH) and other asparaginyl hydroxylases

2004 ◽  
Vol 32 (6) ◽  
pp. 943-945 ◽  
Author(s):  
D.E. Lancaster ◽  
M.A. McDonough ◽  
C.J. Schofield
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Hypoxia Inducible Factor ◽  
Binding Motif ◽  
Iron Binding ◽  
Sequence Analyses ◽  
Hypoxic Response ◽  
Epidermal Growth

FIH (Factor inhibiting hypoxia-inducible factor), an asparaginyl β-hydroxylase belonging to the super-family of 2-oxoglutarate and Fe(II)-dependent dioxygenases, catalyses hydroxylation of Asn-803 of hypoxia-inducible factor, a transcription factor that regulates the mammalian hypoxic response. Only one other asparaginyl β-hydroxylase, which catalyses hydroxylation of both aspartyl and asparaginyl residues in EGF (epidermal growth factor)-like domains, has been characterized. In the light of recent crystal structures of FIH, we compare FIH with the EGFH (EGF β-hydroxylase) and putative asparagine/asparaginyl hydroxylases. Sequence analyses imply that EGFH does not contain the HXD/E iron-binding motif characteristic of most of the 2-oxoglutarate oxygenases.

scholarly journals Synergistic and Multidimensional Regulation of Plasminogen Activator Inhibitor Type 1 Expression by Transforming Growth Factor Type β and Epidermal Growth Factor

2012 ◽  
Vol 287 (15) ◽  
pp. 12520-12528 ◽  
Author(s):  
Xiaoling Song ◽  
Frederic W. Thalacker ◽  
Marit Nilsen-Hamilton
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Plasminogen Activator ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Type I ◽  
Epidermal Growth ◽  
Factor Type ◽  
Activator Inhibitor ◽  
Pai 1

The major physiological inhibitor of plasminogen activator, type I plasminogen activator inhibitor (PAI-1), controls blood clotting and tissue remodeling events that involve cell migration. Transforming growth factor type β (TGFβ) and epidermal growth factor (EGF) interact synergistically to increase PAI-1 mRNA and protein levels in human HepG2 and mink Mv1Lu cells. Other growth factors that activate tyrosine kinase receptors can substitute for EGF. EGF and TGFβ regulate PAI-1 by synergistically activating transcription, which is further amplified by a decrease in the rate of mRNA degradation, the latter being regulated only by EGF. The combined effect of transcriptional activation and mRNA stabilization results in a rapid 2-order of magnitude increase in the level of PAI-1. TGFβ also increases the sensitivity of the cells to EGF, thereby recruiting the cooperation of EGF at lower than normally effective concentrations. The contribution of EGF to the regulation of PAI-1 involves the MAPK pathway, and the synergistic interface with the TGFβ pathway is downstream of MEK1/2 and involves phosphorylation of neither ERK1/2 nor Smad2/3. Synergism requires the presence of both Smad and AP-1 recognition sites in the promoter. This work demonstrates the existence of a multidimensional cellular mechanism by which EGF and TGFβ are able to promote large and rapid changes in PAI-1 expression.

scholarly journals Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Inga Pfeffer ◽  
Lennart Brewitz ◽  
Tobias Krojer ◽  
Sacha A. Jensen ◽  
Grazyna T. Kochan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Conformational Changes ◽  
Cyclic Peptide ◽  
Tetratricopeptide Repeat ◽  
Disulfide Bonding ◽  
Pattern Processing ◽  
Substrate Analogues ◽  
Epidermal Growth

Abstract AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1–3, 2–4, 5–6 disulfide bonding pattern; an unexpected Cys3–4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases.

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