Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small Intestine

Abstract

Protein tyrosine kinase 6 (PTK6) (also called Brk or Sik) is an intracellular tyrosine kinase that is expressed in breast cancer and normal epithelial linings. In adult mice, PTK6 expression is high in villus epithelial cells of the small intestine. To explore functions of PTK6, we disrupted the mouse Ptk6 gene. We detected longer villi, an expanded zone of PCNA expression, and increased bromodeoxyuridine incorporation in the PTK6-deficient small intestine. Although differentiation of major epithelial cell types occurred, there was a marked delay in expression of intestinal fatty acid binding protein, suggesting a role for PTK6 in enterocyte differentiation. However, fat absorption was comparable in wild-type and Ptk6^−/− mice. It was previously shown that the serine threonine kinase Akt is a substrate of PTK6 and that PTK6-mediated phosphorylation of Akt on tyrosine resulted in inhibition of Akt activity. Consistent with these findings, we detected increased Akt activity and nuclear β-catenin in intestines of PTK6-deficient mice and decreased nuclear localization of the Akt substrate FoxO1 in villus epithelial cells. PTK6 contributes to maintenance of tissue homeostasis through negative regulation of Akt in the small intestine and is associated with cell cycle exit and differentiation in normal intestinal epithelial cells.

This work was supported by National Institutes of Health grant DK44525 (to A.L.T.). A.H. received support from the German Academic Exchange Service (DAAD) and the Schering Foundation.

We thank Linda Degenstein for help with generating the mouse model and Deborah Rubin, Andrei Gartel, Helena Palka Hamblin, and Patrick Brauer for helpful comments and suggestions. We thank Jeffrey Gordon for supplying the I-FABP antibody and Hans Clevers and Harry Begthel for their generous support.