Meta-Biol

• Pathways

Mutations in the kinase domain (KD) of ERBB2 result in constitutive activation of ERBB2 signaling, facilitate heterodimerization of ERBB2 with other EGFR family members and increase the signaling intensity, leading to cellular transformation (Kancha et al. 2011).
Only a subset of potential heterodimerization partners has been tested for most ERBB2 KD mutant proteins, so our annotations here are correspondingly limited. ERBB2 L755S and ERBB2 V777L cancer variants were shown to heterodimerize with ERBB3 (HER3) at a higher rate than wild type ERBB2 (Croessmann et al. 2019). Increased activity of ERBB2 L755S, ERBB2 L755P, ERBB2 V777L, ERBB2 D769H, ERBB2 D769Y, ERBB2 V842I, ERBB2 R896C and ERBB2 G778_P780dup in the presence of either EGFR (Kancha et al. 2011, Bose et al. 2013) or ERBB3 (Kancha et al. 2011, Bose et al. 2013, Collier et al. 2013) as a heterodimerization partner was also observed. The interplay of ERBB2 G778_P780dup, ERBB2 I767M and ERBB2 R896C with ERBB3 has not been tested. ERBB2 L869R mutant shows increased activity in the presence of ERBB3, which is further augmented in the presence of dimerization-facilitating ERBB3 E928G mutants (Hanker et al. 2017). The interplay of ERBB2 L869R with EGFR has not been tested. Heterodimerization of ERBB2 KD mutants with ERBB4 has not been tested and ERBB4 is a candidate heterodimerization partner for these KD variants.
ERBB2 H878Y mutant has ten times higher kinase activity than the wild type ERBB2 (Hu, Wan et al. 2015; Hu, Hu et al. 2015), but its heterodimerization properties have not been studied and it is therefore annotated as a candidate.
Ligand requirements have not been studied in the context of heterodimerization of ERBB2 KD mutants, but it is assumed that ligands are required.
The signaling properties of ERBB2 L755M (Gonzalez-Alonso et al. 2015), ERBB2 L755W (COSMIC database: Forbes et al. 2017), ERBB2 V777E (Dietz et al. 2017), ERBB2 V777M (Lee et al. 2006, Ross et al. 2016, Zehir et al. 2017), ERBB2 D769N (Tschui et al. 2015), ERBB2 V842E (Siroy et al. 2015), ERBB2 R896H (Cancer Genome Atlas Research Network 2011), ERBB2 L869Q (Lee et al. 2006) and ERBB2 H878R (Trowe et al. 2008, Zehir et al. 2017) have not been experimentally tested, but they are predicted to be pathogenic (COSMIC database: Forbes et al. 2017) and they are annotated as candidates. ERBB2 T733I (Trowe et al. 2008), ERBB2 T798I (Trowe et al. 2008, Hanker et al. 2017) and ERBB2 T798M (Hanker et al. 2017) usually occur as secondary ERBB2 mutations and are responsible for treatment failure. On their own, ERBB2 T733I and ERBB2 T798I appear to be weakly transforming compared with the other ERBB2 KD mutants. As their signaling properties have been poorly studied, ERBB2 T733I, ERBB2 T798I and ERBB2 T798M are annotated as candidates.
The binding of ERBB2 KD mutants to ERBIN and the HSP90:CDC37 chaperone:co-chaperone complex has not been tested but is assumed to occur similarly to the wild type ERBB2.
Signaling by ERBB2 KD mutants has been organized into subpathways based on the current knowledge of biology of these mutants (heterodimerization, downstream signaling, drug interaction) and on the sequence similarity of their mutations.

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.