Phosphorylated heterodimers of ERBB2 KD mutants recruit GRB2:SOS1 through SHC1

Stable Identifier
Reaction [binding]
Homo sapiens
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For the following ERBB2 KD mutants that were shown to activate RAS/RAF/MAPK signaling, it is assumed that they, like phosphorylated heterodimers of the wild type ERBB2, bind to and phosphorylate SHC1, leading to recruitment of the GRB2:SOS1 complex:

ERBB2 L755P (Kancha et al. 2011);
ERBB2 L755S (Trowe et al. 2008, Kancha et al. 2011, Bose et al. 2013, Cocco et al. 2018);
ERBB2 I767M (Ng et al. 2015);
ERBB2 D769H (Bose et al. 2013);
ERBB2 V777L (Kancha et al. 2011, Bose et al. 2013);
ERBB2 G778_P780dup (Suzawa et al. 2016);
ERBB2 T798I (Hanker et al. 2017);
ERBB2 T798M (Kancha et al. 2011, Rexer et al. 2013);
ERBB2 V842I (Bose et al. 2013);
ERBB2 T862A (Kancha et al. 2011);
ERBB2 L869R (Hanker et al. 2017);
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 G776S (Fan et al. 2008);
ERBB2 Y772_A775dup (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:

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
18039657 Mutational activation of ErbB2 reveals a new protein kinase autoinhibition mechanism

Johnson, RC, Ding, J, Spiridonov, NA, Johnson, GR, Wong, L, Fan, YX

J. Biol. Chem. 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
Normal reaction
Functional status

Gain of function of Phosphorylated heterodimers of ERBB2 KD mutants:p-Y349,Y350-SHC1 [plasma membrane]

Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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