Meta-Biol

• Pathways

ERBB2 extracellular domain (ECD) mutants harbor missense mutations that lead to substitutions of amino acid residues in the heterodimerization arm contact surface, involved in formation of ERBB2 heterodimers. The functionally studied ERBB2 ECD mutants, ERBB2 G309A (Bose et al. 2013), ERBB2 G309E (Greulich et al. 2012) and ERBB2 S310F (Greulich et al. 2012) seem to preferntially heterodimerize with EGFR. Heterodimerization of ERBB2 G309E involves formation of disulfide bonds (Greulich et al. 2012). ERBB2 S310F shows stronger activation of downstream signaling than ERBB2 G309A and ERBB2 G309E, and is hyperphosphorylated on tyrosine residues in the C-tail (Greulich et al. 2012), while the C-tail phosphorylation of ERBB2 G309A (Bose et al. 2013) and ERBB2 G309E (Greulich et al. 2012) is comparable to the wild type ERBB2.
RAS signaling and PLCgamma1 signaling are activated dowsntream of all three ERBB2 ECD mutants, ERBB2 G309A (Bose et al. 2013), ERBB2 G309E (Greulich et al. 2012) and ERBB2 S310F (Greulich et al. 2012), as evidenced by activating phosphorylation on ERKs (MAPK1 and MAPK3) and PLCG1, respectively. ERBB2 G309E and ERBB2 S310F also activate PI3K/AKT signaling, demonstrated by activating phosphorylation of AKT1 (Greulich et al. 2012). Activation of PI3K/AKT signaling downstream of ERBB2 G309A has not been tested. Signaling downstream of ERBB2 S310Y has been poorly characterized and it is annotated as a candidate. Many regulators of cell migration show increased phosphorylation in cells expressing ERBB2 G309E and ERBB2 S310F (Greulich et al. 2012).
Comapred with the wild type ERBB2, ERBB2 G309E, ERBB2 S310F and ERBB2 S310Y are more sensitive to the ERBB2-directed therapeutic antibody trastuzumab (herceptin) and to tyrosine kinase inhibitors lapatinib, neratinib and afatinib (Greulich et al. 2012). ERBB2 G309A was also responsive to trastuzumab, lapatinib and neratinib (Bose et al. 2013).

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.