scholarly journals Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice

2010 ◽  
Vol 207 (8) ◽  
pp. 1617-1624 ◽  
Author(s):  
Athena Chalaris ◽  
Nina Adam ◽  
Christian Sina ◽  
Philip Rosenstiel ◽  
Judith Lehmann-Koch ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Intestinal Barrier ◽  
Systemic Availability ◽  
Epidermal Growth ◽  
Targeting Strategy ◽  
Necrosis Factor ◽  
Increased Susceptibility

The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are not viable. Conditional ADAM17 knockout models demonstrated proinflammatory activities of ADAM17 in septic shock via shedding of TNF. We used a novel gene targeting strategy to generate mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17ex/ex were viable, showed compromised shedding of ADAM17 substrates from the cell surface, and developed eye, heart, and skin defects as a consequence of impaired EGF-R signaling caused by failure of shedding of EGF-R ligands. Unexpectedly, although the intestine of unchallenged homozygous ADAM17ex/ex mice was normal, ADAM17ex/ex mice showed substantially increased susceptibility to inflammation in dextran sulfate sodium colitis. This was a result of impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and, consequently, in defective regeneration of epithelial cells and breakdown of the intestinal barrier. Besides regulating the systemic availability of the proinflammatory cytokine TNF, our results demonstrate that ADAM17 is needed for vital regenerative activities during the immune response. Thus, our mouse model will help investigate ADAM17 as a potential drug target.

scholarly journals iRhom2: An Emerging Adaptor Regulating Immunity and Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6570 ◽  
Author(s):  
Mazin A. Al-Salihi ◽  
Philipp A. Lang
Keyword(s):  
Critical Role ◽  
Growth Factor Receptor ◽  
Biologically Active ◽  
Necrosis Factor Alpha ◽  
Dna Viruses ◽  
Catalytic Center ◽  
Intramembrane Proteases ◽  
Epidermal Growth ◽  
Factor Alpha

The rhomboid family are evolutionary conserved intramembrane proteases. Their inactive members, iRhom in Drosophila melanogaster and iRhom1 and iRhom2 in mammals, lack the catalytic center and are hence labelled “inactive” rhomboid family members. In mammals, both iRhoms are involved in maturation and trafficking of the ubiquitous transmembrane protease a disintegrin and metalloprotease (ADAM) 17, which through cleaving many biologically active molecules has a critical role in tumor necrosis factor alpha (TNFα), epidermal growth factor receptor (EGFR), interleukin-6 (IL-6) and Notch signaling. Accordingly, with iRhom2 having a profound influence on ADAM17 activation and substrate specificity it regulates these signaling pathways. Moreover, iRhom2 has a role in the innate immune response to both RNA and DNA viruses and in regulation of keratin subtype expression in wound healing and cancer. Here we review the role of iRhom2 in immunity and disease, both dependent and independent of its regulation of ADAM17.

scholarly journals The Critical Role of the Epidermal Growth Factor Receptor in Endochondral Ossification

2011 ◽  
Vol 26 (11) ◽  
pp. 2622-2633 ◽  
Author(s):  
Xianrong Zhang ◽  
Valerie A Siclari ◽  
Shenghui Lan ◽  
Ji Zhu ◽  
Eiki Koyama ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Endochondral Ossification ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Epidermal Growth

scholarly journals A crucial role for HVEM and BTLA in preventing intestinal inflammation

2008 ◽  
Vol 205 (6) ◽  
pp. 1463-1476 ◽  
Author(s):  
Marcos W. Steinberg ◽  
Olga Turovskaya ◽  
Raziya B. Shaikh ◽  
Gisen Kim ◽  
Declan F. McCole ◽  
...  
Keyword(s):  
T Cells ◽  
Family Member ◽  
Intestinal Inflammation ◽  
Critical Role ◽  
Binding Partners ◽  
Donor T Cells ◽  
Inflammatory Processes ◽  
Recombination Activating Gene ◽  
Necrosis Factor

The interaction between the tumor necrosis factor (TNF) family member LIGHT and the TNF family receptor herpes virus entry mediator (HVEM) co-stimulates T cells and promotes inflammation. However, HVEM also triggers inhibitory signals by acting as a ligand that binds to B and T lymphocyte attenuator (BTLA), an immunoglobulin super family member. The contribution of HVEM interacting with these two binding partners in inflammatory processes remains unknown. In this study, we investigated the role of HVEM in the development of colitis induced by the transfer of CD4+CD45RBhigh T cells into recombination activating gene (Rag)−/− mice. Although the absence of HVEM on the donor T cells led to a slight decrease in pathogenesis, surprisingly, the absence of HVEM in the Rag−/− recipients led to the opposite effect, a dramatic acceleration of intestinal inflammation. Furthermore, the critical role of HVEM in preventing colitis acceleration mainly involved HVEM expression by radioresistant cells in the Rag−/− recipients interacting with BTLA. Our experiments emphasize the antiinflammatory role of HVEM and the importance of HVEM expression by innate immune cells in preventing runaway inflammation in the intestine.

scholarly journals The ESRP1-GPR137 axis contributes to intestinal pathogenesis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Lukas Franz Mager ◽  
Viktor Hendrik Koelzer ◽  
Regula Stuber ◽  
Lester Thoo ◽  
Irene Keller ◽  
...  
Keyword(s):  
Critical Role ◽  
Intestinal Barrier ◽  
Barrier Integrity ◽  
Regulator Protein ◽  
Intestinal Pathology ◽  
Splicing Regulator ◽  
Inflammatory Bowel ◽  
Intestinal Barrier Integrity ◽  
Increased Susceptibility

Aberrant alternative pre-mRNA splicing (AS) events have been associated with several disorders. However, it is unclear whether deregulated AS directly contributes to disease. Here, we reveal a critical role of the AS regulator epithelial splicing regulator protein 1 (ESRP1) for intestinal homeostasis and pathogenesis. In mice, reduced ESRP1 function leads to impaired intestinal barrier integrity, increased susceptibility to colitis and altered colorectal cancer (CRC) development. Mechanistically, these defects are produced in part by modified expression of ESRP1-specific Gpr137 isoforms differently activating the Wnt pathway. In humans, ESRP1 is downregulated in inflamed biopsies from inflammatory bowel disease patients. ESRP1 loss is an adverse prognostic factor in CRC. Furthermore, generation of ESRP1-dependent GPR137 isoforms is altered in CRC and expression of a specific GPR137 isoform predicts CRC patient survival. These findings indicate a central role of ESRP1-regulated AS for intestinal barrier integrity. Alterations in ESRP1 function or expression contribute to intestinal pathology.

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.

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