Signaling by ERBB2 TMD/JMD mutants

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.

Phosphorylation of tyrosine residues in the C-tail of ERBB2 was shown for the following ERBB2 TMD/JMD mutants:

ERBB2 V659E;

ERBB2 V659K;

ERBB2 G660D;

ERBB2 G660R;

ERBB2 S653C (de Martino et al. 2014 - phosphorylation at Y1248 demonstrated);

ERBB2 R677L;

ERBB2 R678Q (Bose et al. 2013; de Martino et al. 2014 - phosphorylation at Y1248 demonstrated; Pahuja et al. 2018); ERBB2 Q709L

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.

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;

ERBB2 G660D;

ERBB2 G660R;

ERBB2 R678Q;

ERBB2 Q709L;

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.

The following ERBB2 TMD/JMD mutants are sensitive to lapatinib:

ERBB2 S653C (de Martino et al. 2014);

ERBB2 R678Q;

The following ERBB2 TMD/JMD mutants are sensitive to neratinib:

ERBB2 V659E;

ERBB2 G660D;

ERBB2 G660R;

ERBB2 R678Q;

ERBB2 Q709L;

The following ERBB2 TMD/JMD mutants are sensitive to afatinib:

ERBB2 G660D;

ERBB2 G660R;

ERBB2 S653C (de Martino et al. 2014);

ERBB2 R678Q;

ERBB2 Q709L.