共查询到20条相似文献,搜索用时 437 毫秒
1.
Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities 总被引:6,自引:0,他引:6
Transmembrane receptors typically transmit cellular signals following growth factor stimulation by coupling to and activating downstream signaling cascades. Reports of proteolytic processing of cell surface receptors to release an intracellular domain (ICD) has raised the possibility of novel signaling mechanisms directly mediated by the receptor ICD. The receptor tyrosine kinase ERBB4/HER4 (referred to here as ERBB4) undergoes sequential processing by tumor necrosis factor-alpha converting enzyme and presenilin-dependent gamma-secretase to release the ERBB4 ICD (4ICD). Our recent data suggests that regulation of gene expression by the ERBB4 nuclear protein and the proapoptotic activity of ERBB4 involves the gamma-secretase release of 4ICD. To determine the role gamma-secretase processing plays in ERBB4 signaling, we generated an ERBB4 allele with the transmembrane residue substitution V673I (ERBB4-V673I). We demonstrate that ERBB4-V673I fails to undergo processing by gamma-secretase but retains normal cell surface signaling activity. In contrast to wild-type ERBB4, however, ERBB4-V673I was excluded from the nuclei of transfected cells and failed to activate STAT5A stimulation of the beta-casein promoter. These results support the contention that gamma-secretase processing of ERBB4 is necessary to release a functional 4ICD nuclear protein which directly regulates gene expression. We also demonstrate that 4ICD failed to accumulate within mitochondria of ERBB4-V673I transfected cells and the potent proapoptotic activity of ERBB4 was completely abolished in cells expressing ERBB4-V673I. Our results provide the first formal demonstration that proteolytic processing of ERBB4 is a critical event regulating multiple receptor signaling activities. 相似文献
2.
M F Brizzi P Dentelli A Rosso Y Yarden L Pegoraro 《The Journal of biological chemistry》1999,274(24):16965-16972
3.
4.
5.
6.
7.
Sundvall M Korhonen A Vaparanta K Anckar J Halkilahti K Salah Z Aqeilan RI Palvimo JJ Sistonen L Elenius K 《The Journal of biological chemistry》2012,287(27):23216-23226
8.
Expression level-dependent contribution of glucocorticoid receptor domains for functional interaction with STAT5 下载免费PDF全文
Doppler W Windegger M Soratroi C Tomasi J Lechner J Rusconi S Cato AC Almlöf T Liden J Okret S Gustafsson JA Richard-Foy H Starr DB Klocker H Edwards D Geymayer S 《Molecular and cellular biology》2001,21(9):3266-3279
9.
10.
11.
12.
13.
14.
15.
Long W Wagner KU Lloyd KC Binart N Shillingford JM Hennighausen L Jones FE 《Development (Cambridge, England)》2003,130(21):5257-5268
The ERBB family of type 1 receptor tyrosine kinases and their ligands have crucial functions during mammopoiesis, but the signaling networks that ultimately regulate ERBB activity in the breast have remained elusive. Here, we show that mice with Cre-lox mediated deletions of both Erbb4 alleles within the developing mammary gland (Erbb4(Flox/Flox)Wap-Cre) fail to accumulate lobuloalveoli or successfully engage lactation at parturition owing, in part, to impaired epithelial proliferation. Analysis of the mammary differentiation factor STAT5 by immunohistochemistry and western blot revealed a complete ablation of STAT5 activation in Erbb4(Flox/Flox)Wap-Cre mammary epithelium at parturition. Consistent with disrupted STAT5 function, Erbb4(Flox/Flox)Wap-Cre mammary glands at parturition failed to express the mammary epithelial differentiation marker NPT2B. Defects in epithelial functional differentiation at parturition were accompanied by a profound reduction in expression of the STAT5-regulated milk genes casein beta and whey acidic protein. We propose that ERBB4 functions as an essential mediator of STAT5 signaling, and that loss of STAT5 activity contributes to the impaired functional differentiation of mammary glands observed in mice containing conditional Erbb4 deletions. 相似文献
16.
17.
18.
McAveney KM Book ML Ling P Chebath J Yu-Lee L 《Molecular endocrinology (Baltimore, Md.)》2000,14(2):295-306
19.