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Tylosis with Esophageal Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Located on the long arm of chromosome 17 (i.e., 17q25.1), the RHBDF2 gene encodes a catalytically inactive rhomboid (iRhom) protease, iRhom2 (also referred to as RHBDF2 or RHBDL6), one of a family of enzymes possessing a core of six transmembrane helices with the active site residues lying in a hydrophilic cavity [9,10]. Being highly conserved and predominantly expressed in the skin, RHBDF2 (iRhom2) regulates the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (whose substrates include TNF-alpha, amphiregulin [AREG], and HBEGF), inhibits the rhomboid like protease 2 (RHBDL2), which cleaves thrombomodulin at the transmembrane domain, releasing soluble thrombomodulin, and also acts on epidermal growth factor (EGF) [11]. In addition, RHBDF2 modulates the epithelial response to physical stress and injury in the esophagus and skin through its interaction with K16 and its binding partner K6 [12,13].
Angiogenesis and Roles of Adhesion Molecules in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Asmita Hazra, Saptarshi Mandal
In psoriasis, both the leukocytes and the endothelium have been found to have increased stickiness, and this has been attributed to increased adhesion molecules (e.g., Thy1, ICAM1, VCAM1, and MHC II) (Schön and Boehncke 2005), some of which are shed in soluble forms as well. Shedding of ectodomains of some of the adhesion molecules is rapid and part of the leukocyte adhesion process, for example, L-selectin, which can be cleaved either by sheddase/secretase enzymes (e.g., TACE and ADAM17) (Lee and Iruela-Arispe 2008) or “mechanically.” This may explain why the baseline level of soluble l-selectin in health is high (approximately 1.6 μg/mL of soluble L-selectin). For shedding of other adhesion molecules, for example, ICAM1, the soluble form has two sources. One is direct synthesis of the soluble full-length extracellular domain, and the other is the EC domain fragment shed by various proteolytic enzymes, for example, neutrophil elastase or metalloproteases. Soluble monomeric ICAM1 does not significantly inhibit the cellular ICAM1-LFA1 interactions; however, higher-order multimers might potentially compete.
SARS-CoV-2 Morphology, Genomic Organisation and Lifecycle
Published in Srijan Goswami, Chiranjeeb Dey, COVID-19 and SARS-CoV-2, 2022
Srijan Goswami, Ushmita Gupta Bakshi
This section describes how the renin–angiotensin system is related to the human ACE-2 membrane protein that SARS-CoV-2 uses to locate and infect particular cells in the human body for reproduction. In previous sections, we discussed the basic model of an intact human ACE-2 membrane protein. The active form of protein is formed by an additional enzyme called sheddase. Sheddase cleaves the external component of the ACE-2 protein and releases it into the bloodstream. The cleaved ACE-2 then interacts with angiotensin II, converting it into angiotensin 1–7. Angiotensin 1–7 is a powerful antioxidant and vasodilator that dilates the peripheral blood vessel of the body and eliminates the action of angiotensin II on the adrenals. Angiotensin 1–7 lowers the blood pressure and counterbalance the renin–angiotensin system. There is medication that also counteracts the renin–angiotensin system, for example, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) (Wiese et al., 2020; Lanza et al., 2020).ACEIs are industrially synthesised drug molecules that block ACE from transforming angiotensin I to angiotensin II. This drug molecule causes relaxation of blood vessels and thus helps in lowering blood pressure. ACEIs are generally prescribed to patients suffering from hypertension, chronic kidney diseases, cardiac failure and diabetes with associated renal failure. Some common examples are benazepril, captopril and ramipril.ARBs work along the system a little further down the line by blocking angiotensin II from binding to receptors on blood vessels and adrenal glands. Like ACEIs, this drug molecule causes relaxation of blood vessels and thus helps in lowering blood pressure. ARBs are generally prescribed to patients suffering from hypertension, coronary artery disease, cardiac failure and diabetes. Some common examples are telmisartan, olmesartan and eprosartan (Table 2.1).
New insights into glycoprotein Ibα desialylation-mediated platelet clearance
Published in Platelets, 2020
Jack Yule, Neil V. Morgan, Natalie S. Poulter
This recent study involves the injection of neuraminidase derived from Arthrobacter ureafaciens into wildtype mice, which induces a sharp drop in platelet count from 24 hours that slowly recovers over 4–5 days whilst leaving red cell count unaffected, and is consistent with bacterial infections of this type[13]. They observe this same enhanced rate of clearance in both VWF global knockout, a ligand for GPIbα, and a megakaryocyte lineage-specific ADAM17 knockout, a sheddase targeting several membrane proteins, including GPIbα, suggesting they are not involved in this process. However, as there is substrate redundancy within the ADAM metalloprotease family, knocking out only ADAM17 is strong, but not conclusive evidence that there is no role for GPIba shedding in platelet clearance, whereas removal of GPIbα ectodomain (IL4 R-IbaTg: a chimeric construct where the GPIbα ectodomain is replaced with the α subunit of the Interleukin 4 receptor) stunts the increased clearance, maintaining a normal platelet count. Given the absence of this enhanced clearance in IL4 R-IbaTg mice, this supports previous literature which suggests that GPIbα is the major target of this mechanism due to its abundance, high level of glycosylation and therefore sialylation.
Further understanding of glioma mechanisms of pathogenesis: implications for therapeutic development
Published in Expert Review of Anticancer Therapy, 2020
Michael Ruff, Sani Kizilbash, Jan Buckner
A recently described mechanism of a direct neuronal activity to a glioma mitogen link implicates neuronal activity-dependent cleavage on a synaptic-adhesion molecule, neuroligin-3 (NLGN3), which binds to glioma cells similarly as it does for the native oligodendrocyte or oligodendrocyte progenitor cell and stimulates the PIK3-mTOR pathway [56]. NLGN3 sends the glioma cell a mitogenic signal that predominantly facilitates an oligodendrocyte progenitor-cell gene-expression profile pattern. Additionally, NLGN3 offers positive feedback, which results in glioma-cell surface expression of NLGN3, which can then be cleaved. NLGN3 is cleaved from neurons and oligodendrocyte-progenitor cells via ADAM10 sheddase, which can be inhibited by ADAM inhibitors such as INCB3619. ADAM10 sheddase inhibitors prevent the release of neuroligin-3 into the tumor microenvironment and block glioma growth in xenograft models [56]. The association of ADAM10 with glioblastoma-cell migration and invasion has previously been demonstrated. Notably, the up-regulation of ADAM10 sheddase has been demonstrated in more invasive glioblastoma cell lines and in human specimens [57]. The ADAM10-expression levels have correlated with tumor progression as well as the grade of malignancy. Inhibitors of the ADAM family of enzymes have been used in lymphoma and breast cancer [58]. There is very important a direct neuronal activity to glioma link. Clinical trials are to be underway in the very near future with agents targeting ADAM10 in human glioma. Currently, the ADAM10 inhibitor INCB7839 is currently being explored for use in glioma [56].
Specific ADAM10 inhibitors localize in exosome-like vesicles released by Hodgkin lymphoma and stromal cells and prevent sheddase activity carried to bystander cells
Published in OncoImmunology, 2018
Francesca Tosetti, Roberta Venè, Caterina Camodeca, Elisa Nuti, Armando Rossello, Cristina D'Arrigo, Denise Galante, Nicoletta Ferrari, Alessandro Poggi, Maria Raffaella Zocchi
The sheddase activity of ADAMs can also target the so-called “stress molecules”, like the MHC-class-I related MICA and MICB, and the UL16 binding proteins (ULBPs), expressed on cancer cell surface and responsible for inducing an immune response against tumor cells.12,13 This mechanism has been evidenced in chronic lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin and Hodgkin's lymphomas (HL).14-17 In particular, we described overexpression of ADAM10 in the lymph node microenvironment in HL, together with impaired stimulation of T lymphocytes with anti-tumor activity.18 Likewise, CD30 shedding due to ADAM10 activity, has been reported to decrease the efficiency of targeted lymphoma cell killing obtained with monoclonal antibodies in vitro and this effect can be prevented by the use of the inhibitor GI254023X.19 We also developed inhibitors with high specificity for ADAM10 to enhance efficiency and selectivity of action; exposure of HL cells to these inhibitors significantly increases their sensitivity to lymphocyte-mediated killing.20,21