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C1‐TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration
Author(s) -
Hafizi Sassan,
Ibraimi Filiz,
Dahlbäck Björn
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2532fje
Subject(s) - tensin , pten , protein kinase b , microbiology and biotechnology , phosphatase , pi3k/akt/mtor pathway , phosphorylation , signal transduction , biology , mapk/erk pathway , cell growth , kinase , intracellular , chemistry , biochemistry
We have previously identified C1 domain‐containing phosphatase and TENsin homologue (C1‐TEN) as being an intracellular binding partner for Axl receptor tyrosine kinase (RTK). C1‐TEN is a tensin‐related protein that houses an N‐terminal region with predicted structural similarity to PTEN. Here, we report our observations on the effects of ectopic expression of C1‐TEN in HEK293 cells, which resulted in profound molecular and phenotypic changes. Stable expression of C1‐TEN altered cellular morphology, with less cell spreading and weaker filamentous actin staining. Cells overexpressing C1‐TEN were inhibited greatly in their proliferation and migration rates as compared with mock‐transfected cells. Furthermore, serum starvation‐induced apoptosis caused a twofold increase in caspase 3 activity in C1‐TEN‐overexpressing cells vs. mock cells. In addition, C1‐TEN‐overexpressing cells showed a markedly reduced phosphorylation of Akt/PKB kinase and its substrate GSK3, as well as reduced Akt enzymatic activity. No such effects on JNK were observed. Also, serum‐stimulated activation of Akt was delayed in C1‐TEN‐overexpressing cells, while no difference in profile of ERK activation was observed. Furthermore, cells expressing a C1‐TEN mutant where the putative phosphatase active site cysteine at position 231 was substituted for a serine displayed full restoration of both cell proliferation and Akt activation. In conclusion, C1‐TEN appears to be a novel intracellular phosphatase that negatively regulates the Akt/PKB signaling cascade, and is similar to its relative PTEN in this respect. However, the particular domain organization of C1‐TEN may enable it to regulate RTK and other signaling complexes that are linked to Akt/PKB signaling in a unique manner.