PI3K bound to phosphorylated heterodimers of ERBB2 KD mutants and EGFR converts PIP2 to PIP3

Stable Identifier
Reaction [transition]
Homo sapiens
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For the following EGFR-binding ERBB2 KD mutants that were shown to activate PI3K/AKT signaling, it is assumed that heterodimers of these mutants with EGFR, like the wild type ERBB2:EGFR heterodimer, bind to the PI3K complex through GRB2:GAB1, leading to conversion of PIP2 to PIP3:

ERBB2 L755S (Kancha et al. 2011, Cocco et al. 2018, Croessmann et al. 2019);
ERBB2 L755P (Kancha et al. 2011);
ERBB2 I767M (Ng et al. 2015; heterodimerization with EGFR indirectly shown by Bose et al. 2013);
ERBB2 V777L (Kancha et al. 2011);
ERBB2 G778_P780dup (Suzawa et al. 2016);
ERBB2 T798M (Kancha et al. 2011, Rexer et al. 2013);
ERBB2 T798I (Hanker et al. 2017);
ERBB2 T862A (Kancha et al. 2011);
ERBB2 H878Y (Kancha et al. 2011, Hu, Hu et al. 2015, Hu, Wan et al. 2015);
ERBB2 Y772_A775dup (Wang et al. 2006);

Activation of PI3K/AKT 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
30314968 Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer

Formisano, L, Sudhan, DR, Arteaga, CL, Nagy, RJ, Croessmann, S, Kinch, LN, Bernicker, EH, Mathew, A, Gonzalez-Ericsson, PI, Grishin, NV, Lanman, RB, Cutler, RE, Lalani, AS, He, J, Miller, VA, Cristofanilli, M

Clin. Cancer Res. 2019
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
Catalyst Activity

1-phosphatidylinositol-4,5-bisphosphate 3-kinase activity of p-6Y-ERBB2 KD mutants:EGF:p-6Y-EGFR:GRB2:GAB1:PI3K [plasma membrane]

Normal reaction
Functional status

Gain of function of p-6Y-ERBB2 KD mutants:EGF:p-6Y-EGFR:GRB2:GAB1:PI3K [plasma membrane]

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