ERBB2 外周结构域突变体的信号传导
中文名称
通路描述
ERBB2 外周结构域（ECD）突变体携带错义突变，导致异二聚化臂接触面上的氨基酸残基发生取代，该区域参与 ERBB2 异二聚体的形成。功能研究的 ERBB2 ECD 突变体，如 ERBB2 G309A（Bose 等，2013）、ERBB2 G309E（Greulich 等，2012）和 ERBB2 S310F（Greulich 等，2012），似乎倾向于与 EGFR 异二聚化。ERBB2 G309E 的异二聚化涉及二硫键的形成（Greulich 等，2012）。ERBB2 S310F 对下游信号转导的激活程度强于 ERBB2 G309A 和 ERBB2 G309E，并在 C 尾的酪氨酸残基上发生超磷酸化（Greulich 等，2012），而 ERBB2 G309A（Bose 等，2013）和 ERBB2 G309E（Greulich 等，2012）的 C 尾磷酸化与野生型 ERBB2 相当。RAS 信号传导和 PLCγ1 信号传导被所有三种 ERBB2 ECD 突变体激活，这通过激活 ERKs（MAPK1 和 MAPK3）和 PLCG1 的磷酸化证据表明。ERBB2 G309E 和 ERBB2 S310F 还激活 PI3K/AKT 信号传导，通过激活 AKT1 的磷酸化得到证实（Greulich 等，2012）。ERBB2 G309A 下游的 PI3K/AKT 信号传导尚未测试。ERBB2 S310Y 下游的信号传导特征不明确，被注释为候选者。许多细胞迁移调节因子在表达 ERBB2 G309E 和 ERBB2 S310F 的细胞中发生磷酸化增加。与野生型 ERBB2 相比，ERBB2 G309E、ERBB2 S310F 和 ERBB2 S310Y 对靶向 ERBB2 的抗癌抗体 trastuzumab（赫赛汀）和酪氨酸激酶抑制剂 lapatinib、neratinib 和 afatinib 更敏感（Greulich 等，2012）。ERBB2 G309A 也对 trastuzumab、lapatinib 和 neratinib 有反应（Bose 等，2013）。
英文描述
Signaling by ERBB2 ECD mutants 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).
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).
所含基因
11 个基因