Signaling by ERBB2 ECD mutants

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R-HSA-9665348
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Homo sapiens
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ERBB2 extracellular domain (ECD) mutants harbor missense mutations that lead to substitutions of amino acid residues in the heterodimerization arm contact surface, involved in formation of ERBB2 heterodimers. The functionally studied ERBB2 ECD mutants, ERBB2 G309A (Bose et al. 2013), ERBB2 G309E (Greulich et al. 2012) and ERBB2 S310F (Greulich et al. 2012) seem to preferntially heterodimerize with EGFR. Heterodimerization of ERBB2 G309E involves formation of disulfide bonds (Greulich et al. 2012). ERBB2 S310F shows stronger activation of downstream signaling than ERBB2 G309A and ERBB2 G309E, and is hyperphosphorylated on tyrosine residues in the C-tail (Greulich et al. 2012), while the C-tail phosphorylation of ERBB2 G309A (Bose et al. 2013) and ERBB2 G309E (Greulich et al. 2012) is comparable to the wild type ERBB2.
RAS signaling and PLCgamma1 signaling are activated dowsntream of all three ERBB2 ECD mutants, ERBB2 G309A (Bose et al. 2013), ERBB2 G309E (Greulich et al. 2012) and ERBB2 S310F (Greulich et al. 2012), as evidenced by activating phosphorylation on ERKs (MAPK1 and MAPK3) and PLCG1, respectively. ERBB2 G309E and ERBB2 S310F also activate PI3K/AKT signaling, demonstrated by activating phosphorylation of AKT1 (Greulich et al. 2012). Activation of PI3K/AKT signaling downstream of ERBB2 G309A has not been tested. Signaling downstream of ERBB2 S310Y has been poorly characterized and it is annotated as a candidate. Many regulators of cell migration show increased phosphorylation in cells expressing ERBB2 G309E and ERBB2 S310F (Greulich et al. 2012).
Comapred with the wild type ERBB2, ERBB2 G309E, ERBB2 S310F and ERBB2 S310Y are more sensitive to the ERBB2-directed therapeutic antibody trastuzumab (herceptin) and to tyrosine kinase inhibitors lapatinib, neratinib and afatinib (Greulich et al. 2012). ERBB2 G309A was also responsive to trastuzumab, lapatinib and neratinib (Bose et al. 2013).

Literature References
PubMed ID Title Journal Year
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
22908275 Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2

Greulich, H, Kaplan, B, Mertins, P, Chen, TH, Tanaka, KE, Yun, CH, Zhang, X, Lee, SH, Cho, J, Ambrogio, L, Liao, R, Imielinski, M, Banerji, S, Berger, AH, Lawrence, MS, Zhang, J, Pho, NH, Walker, SR, Winckler, W, Getz, G, Frank, D, Hahn, WC, Eck, MJ, Mani, DR, Jaffe, JD, Carr, SA, Wong, KK, Meyerson, M

Proc. Natl. Acad. Sci. U.S.A. 2012
Participants
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Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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