Meta-Biol

• Pathways

Activating mutations in the kinase domain of KIT are found in a small number of cases of AML and melanoma, as well as in myeloproliferative syndromes, mastocytosis and germ cell tumors (Longley et al, 1996; 1999; Nagata et al, 1995; Beghini et al, 2000; Ning et al, 2001; Tian et al, 1999; Kemmer et al, 2004; reviewed in Roskoski, 2018; Meng and Carvajal, 2019). Mutations in the kinase domain and activation loop of KIT (encoded by exons 13, 14 and 17) also arise in gastrointestinal stromal tumors (GIST) as primary mutations (<1%) and as secondary resistance mutations in response to treatment with imatinib (Chen et al, 2004; Serrano et al, 2019; Gajiwala et al, 2008; McLean et al, 2008; reviewed in Antonescu, 2006; Roskoski, 2018; Wu et al, 2019; Corless et al, 2011). Activating kinase mutants of KIT are constitutively active in the absence of ligand and can be tyrosine phosphorylated in the absence of dimerization (Furitsu et al, 1993; Hirota et al, 1998; Tsujimura et al, 1994).

Signaling processes are central to human physiology (e.g., Pires-da Silva & Sommer 2003), and their disruption by either germ-line and somatic mutation can lead to serious disease. Here, the molecular consequences of mutations affecting visual signal transduction and signaling by diverse growth factors are annotated.

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.