Identification of prolidase as a high affinity ligand of the ErbB2 receptor and its regulation of ErbB2 signaling and cell growth.
Identification of prolidase as a high affinity ligand of the ErbB2 receptor and its regulation of ErbB2 signaling and cell growth.
复制标题
DOI：
10.1038/cddis.2014.187
复制
发表时间：
2014-05-08
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
ErbB2, an important membrane-bound receptor tyrosine kinase, was discovered nearly 30 years ago, but a natural ligand has never been found previously. ErbB2 is also an important oncogene and anticancer target, and its overexpression in cancer is associated with poor disease prognosis. Here, we report that human prolidase (PEPD) is a high affinity ligand of ErbB2 and binds as a homodimer to subdomain 3 in the extracellular domain of this receptor. In ErbB2-overexpressing cells, both ErbB2 monomers and activated dimers exist. PEPD bound to ErbB2 monomers relatively slowly but caused ErbB2 dimerization, ErbB2 phosphorylation and downstream signaling. In contrast, PEPD bound rapidly to ErbB2 homodimers and rapidly silenced ErbB2 dimer-Src signaling, a key oncogenic pathway of ErbB2, by disrupting the association of Src with ErbB2. PEPD also caused pronounced ErbB2 depletion, resulting from ErbB2 internalization and degradation. Moreover, PEPD strongly inhibited the DNA synthesis, anchorage-independent growth and invasion and migration of cells that overexpressed ErbB2 but had no effect on cells without ErbB2 overexpression. Cells became sensitized to PEPD upon achieving stable ErbB2 overexpression. Thus, the impact of PEPD on ErbB2 is predominantly inhibitory, and PEPD targets cells addicted to ErbB2. PEPD is also a dipeptidase, but its enzymatic function is not involved in ErbB2 modulation. These findings revise our understanding of ErbB2 and PEPD and may be especially important for combating ErbB2-positive cancers.
登录
查看更多内容
影响因子：
56.9
作者：
COUSSENS, L;YANGFENG, TL;ULLRICH, A
通讯作者：
ULLRICH, A
影响因子：
56.9
作者：
KING, CR;KRAUS, MH;AARONSON, SA
通讯作者：
AARONSON, SA
DOI：
10.1007/s00249-009-0459-4
发表时间：
2010-05-01
影响因子：
2
作者：
Besio, Roberta;Alleva, Stefania;Morante, Silvia
通讯作者：
Morante, Silvia
影响因子：
64.8
作者：
Cho, HS;Mason, K;Leahy, DJ
通讯作者：
Leahy, DJ
影响因子：
11.4
作者：
GrausPorta, D;Beerli, RR;Hynes, NE
通讯作者：
Hynes, NE