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

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

Stable Identifier

R-HSA-9665000

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, plasma membrane

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

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

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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
16843263	HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors Wang, SE, Narasanna, A, Perez-Torres, M, Xiang, B, Wu, FY, Yang, S, Carpenter, G, Gazdar, AF, Muthuswamy, SK, Arteaga, CL	Cancer Cell	2006
18413839	EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformation Trowe, T, Boukouvala, S, Calkins, K, Cutler, RE, Fong, R, Funke, R, Gendreau, SB, Kim, YD, Miller, N, Woolfrey, JR, Vysotskaia, V, Yang, JP, Gerritsen, ME, Matthews, DJ, Lamb, P, Heuer, TS	Clin. Cancer Res.	2008
26375550	Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor Hu, Z, Hu, Y, Liu, X, Xi, R, Zhang, A, Liu, D, Xie, Q, Chen, L	Oncotarget	2015
22046346	Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib Kancha, RK, von Bubnoff, N, Bartosch, N, Peschel, C, Engh, RA, Duyster, J	PLoS ONE	2011
25994018	Intra-tumor genetic heterogeneity and alternative driver genetic alterations in breast cancers with heterogeneous HER2 gene amplification Ng, CK, Martelotto, LG, Gauthier, A, Wen, HC, Piscuoglio, S, Lim, RS, Cowell, CF, Wilkerson, PM, Wai, P, Rodrigues, DN, Arnould, L, Geyer, FC, Bromberg, SE, Lacroix-Triki, M, Penault-Llorca, F, Giard, S, Sastre-Garau, X, Natrajan, R, Norton, L, Cottu, PH, Weigelt, B, Vincent-Salomon, A, Reis-Filho, JS	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, Toyooka, S, Sakaguchi, M, Morita, M, Yamamoto, H, Tomida, S, Ohtsuka, T, Watanabe, M, Hashida, S, Maki, Y, Soh, J, Asano, H, Tsukuda, K, Miyoshi, S	Cancer Sci.	2016
25853726	Phosphorylation of mutationally introduced tyrosine in the activation loop of HER2 confers gain-of-function activity Hu, Z, Wan, X, Hao, R, Zhang, H, Li, L, Li, L, Xie, Q, Wang, P, Gao, Y, Chen, S, Wei, M, Luan, Z, Zhang, A, Huang, N, Chen, L	PLoS ONE	2015
28274957	An Acquired HER2^T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer Hanker, AB, Brewer, MR, Sheehan, JH, Koch, JP, Sliwoski, GR, Nagy, R, Lanman, R, Berger, MF, Hyman, DM, Solit, DB, He, J, Miller, V, Cutler, RE, Lalani, AS, Cross, D, Lovly, CM, Meiler, J, Arteaga, CL	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 Rexer, BN, Ghosh, R, Narasanna, A, Estrada, MV, Chakrabarty, A, Song, Y, Engelman, JA, Arteaga, CL	Clin. Cancer Res.	2013
30301790	Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2) Cocco, E, Javier Carmona, F, Razavi, P, Won, HH, Cai, Y, Rossi, V, Chan, C, Cownie, J, Soong, J, Toska, E, Shifman, SG, Sarotto, I, Savas, P, Wick, MJ, Papadopoulos, KP, Moriarty, A, Cutler, RE, Avogadri-Connors, F, Lalani, AS, Bryce, RP, Chandarlapaty, S, Hyman, DM, Solit, DB, Boni, V, Loi, S, Baselga, J, Berger, MF, Montemurro, F, Scaltriti, M	Sci Signal	2018
23220880	Activating HER2 mutations in HER2 gene amplification negative breast cancer Bose, R, Kavuri, SM, Searleman, AC, Shen, W, Shen, D, Koboldt, DC, Monsey, J, Goel, N, Aronson, AB, Li, S, Ma, CX, Ding, L, Mardis, ER, Ellis, MJ	Cancer Discov	2013