Downregulation of ERBB2 signaling

Stable Identifier
R-HSA-8863795
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

Signaling by ERBB2 can be downregulated by ubiquitination and subsequent proteasome-dependent degradation of ERBB2 or activated ERBB2 heterodimers. In addition, protein tyrosine phosphatases that dephosphorylate tyrosine residues in the C-terminus of ERBB2 prevent the recruitment of adapter proteins involved in signal transduction, thus attenuating ERBB2 signaling.
STUB1 (CHIP) and CUL5 are E3 ubiquitin ligases that can target non-activated ERBB2 for proteasome-dependent degradation (Xu et al. 2002, Ehrlich et al. 2009). RNF41 (NRDP1) is an E3 ubiquitin ligase that targets ERBB3 and activated heterodimers of ERBB2 and ERBB3 for proteasome-dependent degradation by ubiquitinating ERBB3 (Cao et al. 2007).
Two protein tyrosine phosphatases of the PEST family, PTPN12 and PTPN18, dephosphorylate tyrosine residues in the C-terminus of ERBB2, thus preventing signal transduction to RAS and PI3K effectors (Sun et al. 2011, Wang et al. 2014).

Literature References
PubMed ID Title Journal Year
21376233 Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase

Sun, T, Aceto, N, Meerbrey, KL, Kessler, JD, Zhou, C, Migliaccio, I, Nguyen, DX, Pavlova, NN, Botero, M, Huang, J, Bernardi, RJ, Schmitt, E, Hu, G, Li, MZ, Dephoure, N, Gygi, SP, Rao, M, Creighton, CJ, Hilsenbeck, SG, Shaw, CA, Muzny, D, Gibbs, RA, Wheeler, DA, Osborne, CK, Schiff, R, Bentires-Alj, M, Elledge, SJ, Westbrook, TF

Cell 2011
12239347 Chaperone-dependent E3 ubiquitin ligase CHIP mediates a degradative pathway for c-ErbB2/Neu

Xu, W, Marcu, M, Yuan, X, Mimnaugh, E, Patterson, C, Neckers, LM

Proc Natl Acad Sci U S A 2002
25081058 The catalytic region and PEST domain of PTPN18 distinctly regulate the HER2 phosphorylation and ubiquitination barcodes

Wang, HM, Xu, YF, Ning, SL, Yang, DX, Li, Y, Du, YJ, Yang, F, Zhang, Y, Liang, N, Yao, W, Zhang, LL, Gu, LC, Gao, CJ, Pang, Q, Chen, YX, Xiao, KH, Ma, R, Yu, X, Sun, JP

Cell Res. 2014
19933325 Regulation of Hsp90 client proteins by a Cullin5-RING E3 ubiquitin ligase

Ehrlich, ES, Wang, T, Luo, K, Xiao, Z, Niewiadomska, AM, Martinez, T, Xu, W, Neckers, LM, Yu, XF

Proc Natl Acad Sci U S A 2009
17210635 Neuregulin-induced ErbB3 downregulation is mediated by a protein stability cascade involving the E3 ubiquitin ligase Nrdp1

Cao, Z, Wu, X, Yen, L, Sweeney, C, Carraway KL, 3rd

Mol Cell Biol 2007
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