Akt mediated phosphorylation of LARP6; critical step in biosynthesis of type I collagen.

La ribonucleoprotein domain family, member 6 is the RNA binding protein, which regulates translation of collagen mRNAs and synthesis of type I collagen. Posttranslational modifications of and how they affect type I collagen synthesis have not been studied. We show that in lung fibroblasts Lduanyu376 is phosphorylated at 8 serines, 6 of which are located within C-terminal domain. Phosphorylation of Lduanyu376 follows a hierarchical order; S451 phosphorylation being a prerequisite for phosphorylations of other serines. Inhibition of PI3K/Akt pathway reduced the phosphorylation of but had no effect on the S451A mutant, suggesting that PI3K/Akt pathway targets S451 and we have identified Akt as the responsible kinase. Overexpression of S451A mutant had dominant negative effect on collagen biosynthesis; drastically reduced secretion of collagen and induced hyper-modifications of collagen α2 (I) polypeptides. This indicates that Lduanyu376 phosphorylation at S451 is critical for regulating translation and folding of collagen polypeptides. Akt inhibitor, GSK-2141795, which is in clinical trials for treatment of solid tumors, reduced collagen production by human lung fibroblasts with EC50 of 150 nM. This effect can be explained by inhibition of Lduanyu376 phosphorylation and suggests that Akt inhibitors may be effective in treatment of various forms of fibrosis.

KEYWORDS: {{ getKeywords(articleDetailText.words) }}