| First Author | Hambsch B | Year | 2005 |
| Journal | J Biol Chem | Volume | 280 |
| Issue | 16 | Pages | 15888-97 |
| PubMed ID | 15711011 | Mgi Jnum | J:98737 |
| Mgi Id | MGI:3579750 | Doi | 10.1074/jbc.M414359200 |
| Citation | Hambsch B, et al. (2005) {gamma}-Protocadherins, presenilin-mediated release of C-terminal fragment promotes locus expression. J Biol Chem 280(16):15888-97 |
| abstractText | gamma-Protocadherins (gamma-pcdhs) are type I membrane-spanning glycoproteins, widely expressed in the mammal and required for survival. These cell adhesion molecules are expressed from a complex locus comprising 22 functional variable exons arranged in tandem, each encoding extracellular, transmembrane and intracellular sequence, and three exons for an invariant C-terminal domain (gamma-ICD). However, the signaling mechanisms that lie downstream of gamma-pcdhs have not been elucidated. Here we report that gamma-pcdhs are subject to presenilin-dependent intramembrane cleavage (PS-IP), accompanied by shedding of the extracellular domain. The cleaved intracellular domain (gamma-ICD) translocates to the cell nucleus and was detected in subsets of cortical neurons. Notably, gene-targeted mice lacking functional gamma-ICD sequence showed severely reduced gamma-pcdh mRNA levels and neonatal lethality. Most importantly, inhibition of gamma-secretase decreased gamma-pcdh locus expression. Luciferase reporter assays demonstrated that gamma-pcdh promoter activity is increased by gamma-ICD. These results reveal an intracellular signaling mechanism for gamma-pcdhs and identify a novel vital target for the gamma-secretase complex. |
