Meta-Biol

• Pathways

Mutations in the extracellular domain of receptor tyrosine kinases like PDGRFA have the potential to interfere with glycosylation, which is required for proper trafficking to the cell surface. Versions of PDGFRA bearing mutations in the extracellular domain have been identified in some cancers, and while some of these are inactive, some have also been shown to signal constitutively from the endoplasmic reticulum (Ip et al, 2018; Velghe et al, 2014; Ozawa et al, 2010; Paugh et al, 2013; Clarke et al, 2003). PDGFRA Y288C carries a mutation in the extracellular domain of the receptor that prevents the normal trafficking of the protein to the plasma membrane. PDGFRA Y288C is trapped in the endoplasmic reticulum membrane, from where it is able to signal constitutively in the absence of ligand (Ip et al, 2018). Similarly, a version of PDGFRA bearing an in-frame deletion of exons 8 and 9 has been identified in glioblastoma. The resulting protein is constitutively active in the absence of ligand despite the low fraction of protein expressed at the cell surface (Clarke et al, 2003; Ozawa et al, 2010).

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.