scholarly journals The Emerging Role of the FGF/FGFR Pathway in Gastrointestinal Stromal Tumor

2020 ◽  
Vol 21 (9) ◽  
pp. 3313
Author(s):  
Annalisa Astolfi ◽  
Maria Abbondanza Pantaleo ◽  
Valentina Indio ◽  
Milena Urbini ◽  
Margherita Nannini
Keyword(s):  
Growth Factor ◽  
Paracrine Signaling ◽  
Fgf Receptor ◽  
Activating Mutations ◽  
Pathway Activation ◽  
Succinate Dehydrogenase Complex ◽  
Factor Alpha ◽  
Oncogenic Gene ◽  
Mutant Braf

Gastrointestinal stromal tumors (GIST) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. The vast majority are characterized by mutually exclusive activating mutations in KIT or Platelet-derived growth factor alpha (PDGFRA) receptors, or less frequently by succinate dehydrogenase complex (SDH) or NF1 inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 5% of GISTs lack any of such mutations and are called quadruple wild-type (WT) GISTs. Recently, deregulated Fibroblast Growth Factor (FGF)/FGF-receptor (FGFR) signaling emerged as a relevant pathway driving oncogenic activity in different molecular subgroups of GISTs. This review summarizes all the current evidences supporting the key role of the FGF/FGFR pathway activation in GISTs, whereby either activating mutations, oncogenic gene fusions, or autocrine/paracrine signaling have been detected in quadruple WT, SDH-deficient, or KIT-mutant GISTs.

scholarly journals Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Angelica Gualtieri ◽  
Nikolina Kyprianou ◽  
Louise C. Gregory ◽  
Maria Lillina Vignola ◽  
James G. Nicholson ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Critical Role ◽  
Cell Lineage ◽  
Activating Mutations ◽  
Pathway Activation ◽  
Tumour Formation ◽  
Conditional Expression ◽  
Cell Cycle Inhibitors ◽  
Mutation Braf

AbstractGermline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.

Ménétrier disease of childhood: Role of cytomegalovirus and transforming growth factor alpha

1996 ◽  
Vol 128 (2) ◽  
pp. 213-219 ◽  
Author(s):  
Thomas J. Sferra ◽  
Bruce R. Pawel ◽  
Stephen J. Qualman ◽  
B.U.K. Li
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Alpha ◽  
Factor Alpha

scholarly journals Role of Epidermal Growth Factor Receptor (EGFR) and Its Ligands in Kidney Inflammation and Damage

2018 ◽  
Vol 2018 ◽  
pp. 1-22 ◽  
Author(s):  
Sandra Rayego-Mateos ◽  
Raul Rodrigues-Diez ◽  
Jose Luis Morgado-Pascual ◽  
Floris Valentijn ◽  
Jose M. Valdivielso ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Renal Disease ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Therapeutic Strategies ◽  
Egfr Ligands ◽  
Pathway Activation ◽  
Epidermal Growth

Chronic kidney disease (CKD) is characterized by persistent inflammation and progressive fibrosis, ultimately leading to end-stage renal disease. Although many studies have investigated the factors involved in the progressive deterioration of renal function, current therapeutic strategies only delay disease progression, leaving an unmet need for effective therapeutic interventions that target the cause behind the inflammatory process and could slow down or reverse the development and progression of CKD. Epidermal growth factor receptor (EGFR) (ERBB1), a membrane tyrosine kinase receptor expressed in the kidney, is activated after renal damage, and preclinical studies have evidenced its potential as a therapeutic target in CKD therapy. To date, seven official EGFR ligands have been described, including epidermal growth factor (EGF) (canonical ligand), transforming growth factor-α, heparin-binding epidermal growth factor, amphiregulin, betacellulin, epiregulin, and epigen. Recently, the connective tissue growth factor (CTGF/CCN2) has been described as a novel EGFR ligand. The direct activation of EGFR by its ligands can exert different cellular responses, depending on the specific ligand, tissue, and pathological condition. Among all EGFR ligands, CTGF/CCN2 is of special relevance in CKD. This growth factor, by binding to EGFR and downstream signaling pathway activation, regulates renal inflammation, cell growth, and fibrosis. EGFR can also be “transactivated” by extracellular stimuli, including several key factors involved in renal disease, such as angiotensin II, transforming growth factor beta (TGFB), and other cytokines, including members of the tumor necrosis factor superfamily, showing another important mechanism involved in renal pathology. The aim of this review is to summarize the contribution of EGFR pathway activation in experimental kidney damage, with special attention to the regulation of the inflammatory response and the role of some EGFR ligands in this process. Better insights in EGFR signaling in renal disease could improve our current knowledge of renal pathology contributing to therapeutic strategies for CKD development and progression.

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