Meta-Biol

• Pathways

Recurrent missense mutations in regions encoding the transmembrane domain (TMD) and the juxtamembrane domain (JMD) are frequently reported in cancer. The ERBB2 TMD mutants include ERBB2 V659E, ERBB2 V659K, ERBB2 G660D, ERBB2 G660R, ERBB2 S653C, ERBB2 R677L and ERBB2 R678Q. The ERBB2 JMD mutants include ERBB2 E693K and ERBB2 Q709L. ERBB2 TMD mutants ERBB2 V659E, ERBB2 G660D and S653C (de Martino et al. 2014) are known to be activating. ERBB2 TMD/JMD mutants ERBB2 R678Q, ERBB2 E693K, and ERBB2 Q709L mutations may be activating when co-expressed with a wild type ERBB2 receptor (Pahuja et al. 2018). TMD and JMD mutations can activate ERBB2 signaling by improving the active dimer interface or by stabilizing the active conformation. TMD/JMD mutants that are activating in the presence of wild type ERBB2, such as ERBB2 R678Q, may form homodimers with the wild type ERBB2 (Pahuja et al. 2018).

Based on trans-autophosphorylation of ERBB2 and its dimerization partners EGFR and ERBB3, the following ERBB2 TMD/JMD mutants are assumed to form heterodimers with EGFR and ERBB3:
ERBB2 S653C (de Martino et al. 2014)
ERBB2 R678Q (Bose et al. 2013, Pahuja et al. 2018).

Phosphorylation of tyrosine residues in the C-tail of ERBB2 was shown for the following ERBB2 TMD/JMD mutants:
ERBB2 V659E (Pahuja et al. 2018);
ERBB2 V659K (Pahuja et al. 2018);
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 S653C (de Martino et al. 2014 - phosphorylation at Y1248 demonstrated);
ERBB2 R677L (Pahuja et al. 2018);
ERBB2 R678Q (Bose et al. 2013; de Martino et al. 2014 - phosphorylation at Y1248 demonstrated; Pahuja et al. 2018); ERBB2 Q709L (Pahuja et al. 2018)

Phosphorylation of tyrosine residues in the C-tail of EGFR was demonstrated for ERBB2 S653C (de Martino et al. 2014 - phosphorylation at Y1068) and ERBB2 R678Q (Bose et al. 2013; de Martino et al. 2014 - phosphorylation at Y1068).

Phosphorylation of tyrosine residues in the C-tail of ERBB3 was demonstrated for ERBB2 S653C (de Martino et al. 2014 - phosphorylation at Y1197) and ERBB2 R678Q (Bose et al. 2013; de Martino et al. 2014 - phosphorylation at Y1197).

Activation of downstream RAS signaling was shown for ERBB2 S653C (de Martino et al. 2014) and ERBB2 R678Q (Bose et al. 2013, de Martino et al. 2014) through activating tyrosine phosphorylation on ERKs (MAPK1 and MAPK3) and SHC1.

Activation of downstream PLCG1 signaling was demonstrated for ERBB2 R678Q, through activating tyrosine phosphorylation on PLCG1 (Bose et al. 2013).

Activation of PI3K/AKT signaling by ERBB2 TMD/JMD mutants has not been tested.

Signaling by ERBB2 V659K, ERBB2 G660D, ERBB2 G660R, ERBB2 R677L, ERBB2 E693K and ERBB2 Q709L has not been sufficiently studied and they are annotated as candidates.

The following ERBB2 TMD/JMD mutants are sensitive to the therapeutic antibody trastuzumab (herceptin):
ERBB2 V659E (Pahuja et al. 2018);
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 R678Q (Bose et al. 2013, Pahuja et al. 2018);
ERBB2 Q709L (Pahuja et al. 2018);

With respect to pertuzumab, a therapeutic antibody that block ligand-driven heterodimerization of ERBB2, ERBB2 R678Q is sensitive to pertuzumab, while ERBB2 V659E, ERBB2 G660D, ERBB2 G660R and probably ERBB2 Q709L are resistant (Pahuja et al. 2018).

The following ERBB2 TMD/JMD mutants are sensitive to lapatinib:
ERBB2 S653C (de Martino et al. 2014);
ERBB2 R678Q (Bose et al. 2013);

The following ERBB2 TMD/JMD mutants are sensitive to neratinib:
ERBB2 V659E (Pahuja et al. 2018);
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 R678Q (Bose et al. 2013, Pahuja et al. 2018);
ERBB2 Q709L (Pahuja et al. 2018);

The following ERBB2 TMD/JMD mutants are sensitive to afatinib:
ERBB2 G660D (Pahuja et al. 2018);
ERBB2 G660R (Pahuja et al. 2018);
ERBB2 S653C (de Martino et al. 2014);
ERBB2 R678Q (Pahuja et al. 2018);
ERBB2 Q709L (Pahuja et al. 2018).

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.