Downregulation of Fer Tyrosine Kinase Signaling Increases a-dystroglycan-mediated Cell Adhesion Thereby Suppresses Tumor Formation

Glycans of α-dystroglycan (α-DG), which is expressed at the epithelial cell-basement membrane (BM) interface, play an essential role in epithelium development and tissue organization. Laminin-binding glycans on α-DG expressed on cancer cells suppress tumor progression by attenuating tumor cell migration signal from the BM (1,2). However, mechanisms controlling laminin-binding glycan expression are not known yet. Here, we used siRNA library screening and identified Fer kinase, a non-receptor type tyrosine kinase, as a key regulator of laminin-binding glycan expression. Fer overexpression decreased laminin-binding glycan expression, while siRNA-mediated knockdown of Fer kinase increased glycan expression on breast and prostate cancer cell lines. Loss of Fer kinase function via siRNA or mutagenesis increased transcription levels of glycosyltransferases, including POMT1, β3GnT1, and LARGE, which are required to synthesize laminin-binding glycans. Consistently, inhibition of Fer expression increases laminin-binding glycan thereby decreases cell migration in the presence of laminin fragment. Fer kinase regulates STAT3 phosphorylation and consequent activation, and knockdown of STAT3 increased laminin-binding glycan expression on cancer cells. However, expression or knockdown of Fes, which is highly similar to Fer, does not affect the expression of the laminin-binding glycans. These results indicate that Fer tyrosine kinase specifically downregulates laminin-binding glycans, thereby increases cell migration. The results also suggest that Fer kinase is an excellent target for downregulation of tumor progression and treatment of muscular dystrophy. Supported by NIH/NCI grant PO1 CA71932.

References

1. Bao X, Kobayashi M, Hatakeyama S, Angata K, Gullberg D, Nakayama J, Fukuda MN, Fukuda M. Tumor suppressor function of laminin-binding α-dystroglycan requires a distinct β3-N-acetylglucosaminyltransferase. Proc Natl Acad Sci U S A; 106:12109–12114, 2009.

2. Shimojo H, Kobayashi M, Kamigaito T, Shimojo Y, Fukuda M, Nakayama J. Reduced glycosylation of α-dystroglycans on carcinoma cells contributes to formation of highly infiltrative histological patterns in prostate cancer. The Prostate; 71, 1151–1157, 2011.