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Hereditary Papillary Renal Cell Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Germline mutations in the MET gene destabilize the inactive (or stabilize the active) MET kinase conformation, leading to ligand-independent constitutive kinase activation. For example, mutations in the Sema domain likely affect the structure of the ligand-binding domain, resulting in the receptor activity of MET independent of HGF and increased activation of downstream genes. Mutations in the JM domain attenuate MET receptor ubiquitination and degradation and prolong MET signaling, leading to subsequent overactivation. Missense variants (e.g., M1149 T, V1206L, V1238I, D1246N, and Y1248C) in the regions that flank the critical tyrosine residues Y1234 and Y1235 within the kinase domain constitutively activate the MET protein. Further, point mutations in the multifunctional docking site affect signal transduction. Overall, MET amplification and overexpression promote oncogenesis, angiogenesis, and metastasis [10–12].
Amivantamab for the treatment of EGFR exon 20 insertion mutant non-small cell lung cancer
Published in Expert Review of Anticancer Therapy, 2022
The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved by Neijssen et al. to better understand the mechanism of MET inhibition [69]. Amivantamab binds to a particular extracellular region of MET known as the Sema domain, which is required for HGF-induced receptor dimerization and activation [76]. The large interface of the Fab domain of amivantamab with the Sema domain of MET blocks binding of the β-chain of HGF to MET and therefore prevents ligand-induced activation. Mapping of the EGFR epitope bound by amivantamab was performed by a combination of site-directed mutagenesis and flow cytometry binding assays to identify residues K443, K465, I467, and S468 in the extracellular EGFR domain III, which shows partial overlap with the epitope bound by the mAb cetuximab [76].
Semaphorin-3A and Netrin-1 predict the development of kidney injury in children with congenital hydronephrosis
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2018
Xiaobing Li, Xianghua Liu, Ji Li, ELi Song, Ning Sun, Wen Liu, Tian Wang, Jinchang Yang, Zhenzhen Li
Semaphorins are secreted or membrane-associated glycoproteins found in eight classes based upon their structure elements and amino acid sequences. Class 3 semaphorins are secreted, classes 4 through 6 are transmembrane proteins and class 7 are membrane associated via glycosylphosphatidylinositol (GPI) linkage. They are characterized structurally by a conserved ∼400 amino acid sema domain [6]. Semaphorins are classically described as collapsing factors and mediators of axon repulsion, although they may also act as context-dependent chemoattractants. Semaphorin-3A (SEMA-3A) is a chemorepellent with multiple guidance functions, including axon pathfinding, cardiac and peripheral vascular patterning, and branching morphogenesis [7]. Semaphorin-3A expression persists in adult podocytes and collecting tubules [8,9], and is highly induced after an acute tubular injury, leading to increased excretion of SEMA-3A in urine in both mice and humans [10–12]. Urinary SEMA-3A (uSEMA-3A) is a very early and sensitive biomarker of kidney injury, and various studies have reported that uSEMA-3A levels are significantly increased in AKI, diabetic nephropathy and non-diabetic hypertensive patients with CKD [10,13].
Identification of a novel de novo variant in OTX2 in a patient with congenital microphthalmia using targeted next-generation sequencing followed by prenatal diagnosis
Published in Ophthalmic Genetics, 2022
Maryam Rafati, Faezeh Mohamadhashem, Koosha Jalilian, Fatemeh Hoseininasab, Laya Fakhri, Azadeh Hoseini, Hosna Amiri, Zeinab Barati, Somayeh Darzi Ramandi, Nioosha Mostofinezhad, Amir Hosein Mahmoudi, Saeed Reza Ghaffari
The SEMA4A gene encodes a member of the semaphorin family of transmembrane proteins and is composed of 15 exons. The Sema4A protein has a critical function in immune cells and retinal systems as well as angiogenesis and carcinogenesis (25). This protein contains 760 amino acids and consists of a sema domain, a PSI domain, an immunoglobulin-like C2 type domain, and a helical cytoplasmic tail. Pathogenic variants in SEMA4A are associated with retinal degenerative diseases, most notably retinitis pigmentosa and cone rod dystrophy (26). The patient harbored the c.1480C>T (p. Arg494Ter) variant in exon 13 of this gene, leading to a premature stop codon just before the PSI domain.