Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind GRB2:SOS1

Stable Identifier
R-HSA-9665000
Type
Reaction
Species
Homo sapiens
Compartment
cytosol, plasma membrane
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Phosphorylated heterodimers of ERBB2 KD mutants and EGFR bind GRB2:SOS1
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The following EGFR-binding ERBB2 KD mutants that were shown to activate RAS/RAF/MAPK signaling, evidenced by activating phosphorylation of ERKs (MAPK1 and MAPK3), are assumed to, like the wild type ERBB2:EGFR heterodimer, directly bind to the GRB2:SOS1 complex:

ERBB2 L755S (Trowe et al. 2008, Kancha et al. 2011, Bose et al. 2013, Cocco et al. 2018);
ERBB2 L755P (Kancha et al. 2011);
ERBB2 I767M (Ng et al. 2015; binding to EGFR indirectly demonstrated by Bose et al. 2013);
ERBB2 D769H (Bose et al. 2013);
ERBB2 V777L (Kancha et al. 2011, Bose et al. 2013);
ERBB2 P780_Y781insGSP (Suzawa et al. 2016);
ERBB2 T798M (Kancha et al. 2011, Rexer et al. 2013);
ERBB2 T798I (Hanker et al. 2017);
ERBB2 V842I (Bose et al. 2013);
ERBB2 T862A (Kancha et al. 2011);
ERBB2 H878Y (Kancha et al. 2011, Hu, Hu et al. 2015, Hu, Wan et al. 2015);
ERBB2 R896C (Bose et al. 2013);
ERBB2 L755_T759del (Bose et al. 2013);
ERBB2 A775_G776insYVMA (Wang et al. 2006);

Activation of RAS/RAF/MAPK signaling downstream of the following ERBB2 KD cancer mutants has not been studied and they are annotated as candidates:

ERBB2 L755M
ERBB2 L755W
ERBB2 D769Y
ERBB2 D769N
ERBB2 V777M
ERBB2 V777E
ERBB2 T733I
ERBB2 V842E
ERBB2 H878R
ERBB2 R896H
ERBB2 G778_P780insGSP
ERBB2 A771_Y772insYVMA

Literature References
PubMed ID Title Journal Year
18413839 EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation

Trowe, T, Fong, R, Woolfrey, JR, Lamb, P, Yang, JP, Gerritsen, ME, Cutler, RE, Miller, N, Vysotskaia, V, Funke, R, Kim, YD, Gendreau, SB, Heuer, TS, Boukouvala, S, Matthews, DJ, Calkins, K

Clin. Cancer Res. 2008
16843263 HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors

Muthuswamy, SK, Xiang, B, Gazdar, AF, Arteaga, CL, Narasanna, A, Yang, S, Carpenter, G, Perez-Torres, M, Wu, FY, Wang, SE

Cancer Cell 2006
26375550 Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor

Xi, R, Hu, Z, Liu, X, Xie, Q, Chen, L, Zhang, A, Liu, D, Hu, Y

Oncotarget 2015
22046346 Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib

Duyster, J, Kancha, RK, Engh, RA, Peschel, C, Bartosch, N, von Bubnoff, N

PLoS ONE 2011
25994018 Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification

Geyer, FC, Wai, P, Wilkerson, PM, Penault-Llorca, F, Arnould, L, Ng, CK, Gauthier, A, Norton, L, Reis-Filho, JS, Cowell, CF, Weigelt, B, Martelotto, LG, Sastre-Garau, X, Wen, HC, Giard, S, Lacroix-Triki, M, Cottu, PH, Lim, RS, Natrajan, R, Bromberg, SE, Piscuoglio, S, Rodrigues, DN, Vincent-Salomon, A

Genome Biol. 2015
26545934 Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations

Suzawa, K, Hashida, S, Watanabe, M, Ohtsuka, T, Tomida, S, Maki, Y, Asano, H, Miyoshi, S, Morita, M, Tsukuda, K, Soh, J, Toyooka, S, Sakaguchi, M, Yamamoto, H

Cancer Sci. 2016
25853726 Phosphorylation of mutationally introduced tyrosine in the activation loop of HER2 confers gain-of-function activity

Hao, R, Wang, P, Hu, Z, Li, L, Zhang, A, Chen, S, Gao, Y, Luan, Z, Zhang, H, Huang, N, Wan, X, Wei, M, Xie, Q, Chen, L, Li, L

PLoS ONE 2015
28274957 An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer

Hyman, DM, Solit, DB, Nagy, R, Sheehan, JH, Sliwoski, GR, Berger, MF, He, J, Lalani, AS, Brewer, MR, Miller, V, Cross, D, Cutler, RE, Hanker, AB, Lanman, R, Arteaga, CL, Koch, JP, Lovly, CM, Meiler, J

Cancer Discov 2017
23948973 Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2

Song, Y, Estrada, MV, Arteaga, CL, Chakrabarty, A, Narasanna, A, Ghosh, R, Rexer, BN, Engelman, JA

Clin. Cancer Res. 2013
30301790 Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

Cutler, RE, Papadopoulos, KP, Loi, S, Avogadri-Connors, F, Javier Carmona, F, Scaltriti, M, Soong, J, Boni, V, Bryce, RP, Baselga, J, Chan, C, Toska, E, Chandarlapaty, S, Savas, P, Montemurro, F, Cownie, J, Cai, Y, Moriarty, A, Cocco, E, Razavi, P, Rossi, V, Lalani, AS, Berger, MF, Shifman, SG, Solit, DB, Wick, MJ, Won, HH, Hyman, DM, Sarotto, I

Sci Signal 2018
23220880 Activating HER2 mutations in HER2 gene amplification negative breast cancer

Bose, R, Shen, W, Aronson, AB, Goel, N, Koboldt, DC, Li, S, Searleman, AC, Ma, CX, Ellis, MJ, Shen, D, Ding, L, Monsey, J, Mardis, ER, Kavuri, SM

Cancer Discov 2013
Participants
Input
Output
Participates
as an event of
Normal reaction
GRB2:SOS1 complex binds phosphorylated EGFR:ERBB2 heterodimer (Homo sapiens)
Functional status

Gain of function of p-6Y-ERBB2 KD mutants:EGF:p-6Y-EGFR [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Orlic-Milacic, M  (2019-07-31)
Reviewed
Kancha, RK  (2019-09-15)
Created
Orlic-Milacic, M  (2019-10-28)
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