Meta-Biol

• Pathways

FLT3 is subject to internal tandem duplications (ITDs) of lengths varying from 3 to 1236 base pairs (Nakao et al, 1996; Kiyoi et al 1997, Meshinchi et al, 2008; reviewed in Kazi and Roonstrand, 2019). These ITDs are generally found in the juxtamembrane domain, or more rarely, the first tyrosine kinase domain (TKD) and disrupt the autoinhibitory loop of the receptor, constitutively activating it (Kiyoi et al, 2002; Griffith et al, 2004; reviewed in Lagunas-Rangel and Chavez-Valencia, 2017; Kazi and Roonstrand, 2019). FLT3 ITDs are found in ~25% of acute myeloid leukemias (AMLs) and represent the most frequent mutation of this cancer (reviewed in Kazi and Roonstrand, 2019, Klug et al, 2018)
At lower frequency, FLT3 is subject to activating point mutations (~7% of AML cases). These mutations tend to cluster in the TKD, with mutation of the activation loop residue D835 and the gatekeeper F691 residue the most common sites (Griffin et al, 2001; Jiang et al, 2004; reviewed in Kazi and Roonstrand, 2019).
FLT3 ITD and TKD mutants support cellular transformation through activation of downstream signaling pathways such as the MAP kinase, PI3K/AKT and STAT5 cascades. There is some debate about the extent to which the pathways activated by the ITD and TKD mutants are distinct, with some evidence that STAT5 signaling, in particular, is more characteristic of FLT3 ITD activation (Hayakawa et al, 2000; Choudhary et al, 2005; Grundler et al, 2005; Choudhary et al, 2007; Yoshimoto et al, 2009; Leischner et al, 2012; Janke et al, 2014; Marhall et al, 2018; reviewed in Chan, 2011; Kazi and Roonstrand, 2019).

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.