Signaling by ERBB2 KD Mutants

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Homo sapiens
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Mutations in the kinase domain (KD) of ERBB2 result in constitutive activation of ERBB2 signaling, facilitate heterodimerization of ERBB2 with other EGFR family members and increase the signaling intensity, leading to cellular transformation (Kancha et al. 2011).
Only a subset of potential heterodimerization partners has been tested for most ERBB2 KD mutant proteins, so our annotations here are correspondingly limited. ERBB2 L755S and ERBB2 V777L cancer variants were shown to heterodimerize with ERBB3 (HER3) at a higher rate than wild type ERBB2 (Croessmann et al. 2019). Increased activity of ERBB2 L755S, ERBB2 L755P, ERBB2 V777L, ERBB2 D769H, ERBB2 D769Y, ERBB2 V842I, ERBB2 R896C and ERBB2 P780_Y781insGSP in the presence of either EGFR (Kancha et al. 2011, Bose et al. 2013) or ERBB3 (Kancha et al. 2011, Bose et al. 2013, Collier et al. 2013) as a heterodimerization partner was also observed. The interplay of ERBB2 P780_Y781insGSP, ERBB2 I767M and ERBB2 R896C with ERBB3 has not been tested. ERBB2 L869R mutant shows increased activity in the presence of ERBB3, which is further augmented in the presence of dimerization-facilitating ERBB3 E928G mutants (Hanker et al. 2017). The interplay of ERBB2 L869R with EGFR has not been tested. Heterodimerization of ERBB2 KD mutants with ERBB4 has not been tested and ERBB4 is a candidate heterodimerization partner for these KD variants.
ERBB2 H878Y mutant has ten times higher kinase activity than the wild type ERBB2 (Hu, Wan et al. 2015; Hu, Hu et al. 2015), but its heterodimerization properties have not been studied and it is therefore annotated as a candidate.
Ligand requirements have not been studied in the context of heterodimerization of ERBB2 KD mutants, but it is assumed that ligands are required.
The signaling properties of ERBB2 L755M (Gonzalez-Alonso et al. 2015), ERBB2 L755W (COSMIC database: Forbes et al. 2017), ERBB2 V777E (Dietz et al. 2017), ERBB2 V777M (Lee et al. 2006, Ross et al. 2016, Zehir et al. 2017), ERBB2 D769N (Tschui et al. 2015), ERBB2 V842E (Siroy et al. 2015), ERBB2 R896H (Cancer Genome Atlas Research Network 2011), ERBB2 L869Q (Lee et al. 2006) and ERBB2 H878R (Trowe et al. 2008, Zehir et al. 2017) have not been experimentally tested, but they are predicted to be pathogenic (COSMIC database: Forbes et al. 2017) and they are annotated as candidates. ERBB2 T733I (Trowe et al. 2008), ERBB2 T798I (Trowe et al. 2008, Hanker et al. 2017) and ERBB2 T798M (Hanker et al. 2017) usually occur as secondary ERBB2 mutations and are responsible for treatment failure. On their own, ERBB2 T733I and ERBB2 T798I appear to be weakly transforming compared with the other ERBB2 KD mutants. As their signaling properties have been poorly studied, ERBB2 T733I, ERBB2 T798I and ERBB2 T798M are annotated as candidates.
The binding of ERBB2 KD mutants to ERBIN and the HSP90:CDC37 chaperone:co-chaperone complex has not been tested but is assumed to occur similarly to the wild type ERBB2.
Signaling by ERBB2 KD mutants has been organized into subpathways based on the current knowledge of biology of these mutants (heterodimerization, downstream signaling, drug interaction) and on the sequence similarity of their mutations.

Literature References
PubMed ID Title Journal Year
26287187 Pyrosequencing-Based Assays for Rapid Detection of HER2 and HER3 Mutations in Clinical Samples Uncover an E332E Mutation Affecting HER3 in Retroperitoneal Leiomyosarcoma

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Int J Mol Sci 2015
28481359 Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients

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Nat. Med. 2017
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
16397024 Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas

Park, CH, Nam, SW, Kim, SY, Park, K, Kim, SH, Lee, JY, Lee, SH, Seo, SH, Soung, YH, Yoo, NJ, Park, WS, Wang, YP, Lee, JW

Clin. Cancer Res. 2006
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
27899578 COSMIC: somatic cancer genetics at high-resolution

Sondka, Z, Bamford, S, Campbell, PJ, De, T, Kok, CY, Ponting, L, Thompson, S, Jubb, H, Tate, J, Beare, D, Ward, S, Cole, CG, Harsha, B, Boutselakis, H, Bindal, N, Dawson, E, Forbes, SA, Stefancsik, R, Jia, M

Nucleic Acids Res. 2017
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
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
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
25809292 Morphological and molecular characteristics of HER2 amplified urothelial bladder cancer

Rotzer, D, Seiler, R, Baumgartner, U, Bandi, N, Genitsch, V, Fleischmann, A, Tschui, J, Vassella, E, Thalmann, GN

Virchows Arch. 2015
29088767 Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy

Reisinger, E, Jäger, D, Riediger, AL, Dietz, S, Grüllich, C, Volckmar, AL, Stenzinger, A, Pahernik, S, Schlesner, M, Duensing, S, Du, Y, Hohenfellner, M, Sültmann, H

Oncotarget 2017
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
25148578 Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma

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J. Invest. Dermatol. 2015
30301790 Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

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Sci Signal 2018
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Genome Biol. 2015
27284958 Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies

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Cancer 2016
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

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21720365 Integrated genomic analyses of ovarian carcinoma

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Nature 2011
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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