ERBB2 KD mutants trans-autophosphorylate

Stable Identifier
R-HSA-9664588
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol, plasma membrane, extracellular region
ReviewStatus
5/5
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ERBB2 KD mutants trans-autophosphorylate
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The following ERBB2 KD mutants were shown to undergo trans-autophosphorylation in the presence of EGFR:

ERBB2 L755P (Bose et al. 2013);
ERBB2 L755S (Kancha et al. 2011, Bose et al. 2013);
ERBB2 I767M (Bose et al. 2013);
ERBB2 D769H (Bose et al. 2013);
ERBB2 D769Y (Bose et al. 2013);
ERBB2 V777L (Kancha et al. 2011, Bose et al. 2013);
ERBB2 G778_P780dup (Bose et al. 2013, Suzawa et al. 2016, Ogoshi et al. 2019);
ERBB2 T798M (Kancha et al. 2011, Rexer et al. 2013)
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 Y772_A775dup (Wang et al. 2006)

The following ERBB2 KD mutants were shown to undergo trans-autophosphorylation in the presence of ERBB3:

ERBB2 L755P (Bose et al. 2013);
ERBB2 L755S (Kancha et al. 2011, Bose et al. 2013);
ERBB2 I767M (Ng et al. 2015 – indirect, in response to neuregulin-1 (NRG1) treatment);
ERBB2 D769H (Bose et al. 2013, Collier et al. 2013);
ERBB2 D769Y (Bose et al. 2013, Collier et al. 2013);
ERBB2 V777L (Kancha et al. 2011, Bose et al. 2013);
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 G776S (Fan et al. 2008);
ERBB2 Y772_A775dup (Wang et al. 2006)

In the majority of studies, trans-autophosphorylation of specific tyrosine residues of ERBB2 KD mutants and its heterodimerization partners, EGFR and ERBB3 (and ERBB4), has not been examined, and they are assumed to be identical to tyrosine residues that undergo trans-autophosphorylation in the wild type ERBB2 heterodimers. ERBB2 H878Y is also phosphorylated on the substitution tyrosine Y878 (Hu, Wan et al. 2015). EGFR and ERBB3 undergo trans-autophosphorylation in the presence of ERBB2 L755_T759del mutant, while ERBB2 L755_T759del remains unphosphorylated (Bose et al. 2013).

Phosphorylation at tyrosine Y1221 was demonstrated for the following ERBB2 KD mutants:
ERBB2 L755S (Trowe et al. 2008);
ERBB2 T798I (Hanker et al. 2017);
ERBB2 L869R (Hanker et al. 2017);

Phosphorylation at tyrosine Y1222 was demonstrated for the following ERBB2 KD mutants:
ERBB2 L755S (Trowe et al. 2008);
ERBB2 T798I (Hanker et al. 2017);
ERBB2 L869R (Hanker et al. 2017);

Phosphorylation at tyrosine Y1248 was demonstrated for the following ERBB2 KD mutants:
ERBB2 L755S (Croessmann et al. 2019);
ERBB2 V777L (Croessmann et al. 2019);
ERBB2 T798M (Rexer et al. 2013);
ERBB2 T798I (Hanker et al. 2017);
ERBB2 L869R (Hanker et al. 2017);
ERBB2 Y772_A775dup (Wang et al. 2006);

Phosphorylation of EGFR at tyrosine Y1068 was demonstrated in the presence of the following ERBB2 KD mutants:
ERBB2 T798M (Rexer et al. 2013);
ERBB2 Y772_A775dup (Wang et al. 2006)

Phosphorylation of ERBB3 at tyrosine Y1197 was demonstrated in the presence of the following ERBB2 KD mutants:
ERBB2 L755S (Croessmann et al. 2019);
ERBB2 V777L (Croessmann et al. 2019);
ERBB2 T798M (Rexer et al. 2013);
ERBB2 L869R (Hanker et al. 2017);
Phosphorylation of ERBB3 at tyrosine Y1289 was demonstrated in the presence of the following ERBB2 KD mutants:
ERBB2 Y772_A775dup (Wang et al. 2006, Minami et al. 2007);

Trans-autophosphorylation of the following ERBB2 KD mutants has not been studied and they are annotated as candidates:
ERBB2 L755M
ERBB2 L755W
ERBB2 D769N
ERBB2 V777M
ERBB2 V777E
ERBB2 T733I
ERBB2 V842E
ERBB2 L869Q
ERBB2 H878R
ERBB2 R896H
ERBB2 G776C
ERBB2 G776L
ERBB2 G776V

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
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
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
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
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
17311002 The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272

Meyerson, M, Thomas, RK, Wong, KK, Weir, BA, Haringsma, HJ, Lee, JC, Liniker, E, Shimamura, T, Shapiro, GI, Glatt, KA, LaFramboise, T, Minami, Y, Lowell, AM, Borgman, CL, Feng, W, Wolf, J, Shah, K

Oncogene 2007
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
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
23843458 Carboxyl group footprinting mass spectrometry and molecular dynamics identify key interactions in the HER2-HER3 receptor tyrosine kinase interface

Monsey, J, Collier, TS, Diraviyam, K, Sept, D, Shen, W, Bose, R

J. Biol. Chem. 2013
30854046 Anti-tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations

Suzawa, K, Kurihara, E, Sato, H, Yoshioka, T, Takahashi, Y, Tomida, S, Shien, K, Ogoshi, Y, Torigoe, H, Namba, K, Soh, J, Toyooka, S, Sakaguchi, M, Yamamoto, H

Oncol Lett 2019
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
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
Participants
Input
Output
Participates
as an event of
Catalyst Activity

protein tyrosine kinase activity of Heterodimers of ERBB2 KD mutants [plasma membrane]

Physical Entity
Heterodimers of ERBB2 KD mutants [plasma membrane] (Homo sapiens)
Activity
protein tyrosine kinase activity (GO:0004713)
This event is regulated
Negatively by
Regulator
ERBB2 KD mutants (trastuzumab sensitive):trastuzumab:ERBIN:HSP90:CDC37 [plasma membrane] (Homo sapiens)
Active Unit
Lapatinib [cytosol]
trastuzumab [extracellular region]
Regulator
ERBB2 KD mutants:TKIs:ERBIN:HSP90:CDC37 [plasma membrane] (Homo sapiens)
Active Unit
TKIs (ERBB2) [cytosol]
Normal reaction
Trans-autophosphorylation of ERBB2 heterodimers (Homo sapiens)
Functional status

Gain of function of Heterodimers of ERBB2 KD mutants [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  (2019-09-16)
Created
Orlic-Milacic, M  (2019-10-25)
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