FAK-Mediated Src phosphorylation of Endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation

Dev Cell. 2005 Aug; 9(2): 185-96

Speaker: 翁子玉                              Time: 3/22/2006 14:10~15:00

Commentator: 鄭宏祺 老師                               Place: Room 601

Abstract:

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays an important role in integrin-mediated signaling pathways¹. FAK kinase activity is needed to promote invasive cell motility and the phosphorylation of Tyr-397 functions to enhance the recruitment of activated Src. Recent studies show that membrane type-I matrix metalloproteinase (MT1-MMP) could be a key enzyme for tumor invasion and its expression on the cell surface plays important roles in the activation of other MMPs². Here, the authors wanted to explore how FAK regulate the expression of MT1-MMP and cause the degradation of extracellular matrix. They used a v-Src-transformed cells which can activate a FAK-dependent mechanism that attenuates endocytosis of MT1-MMP. The authors first observed that the surface expression of MT1-MMP was higher in the FAK^+/+Src cells compared with the FAK^-/- Src cells. Reduced endocytosis of MT1-MMP regulated by FAK might be the potential mechanism. This led the authors to investigate the role of Endophilin A2 which is an endocytosis-associated³ protein in this mechanism. They found that C-terminal Pro-rich motif of FAK could interact with the SH3 domain of Endophilin A2. This binding allowed FAK to act as a scaffolding protein⁴ to recruit Src, then Src could phosphory Endophilin A2 at Try315. This phosphorylation at Try315 of Endophilin A2 reduced its interaction with dynamin, which led to reduced endocytosis of MT1-MMP. All together, the authors proposed a mechanism that FAK could increase surface expression of MT1-MMP by inhibiting Endophilin A2 binding to dynamin, and caused the degradation of extracellular matrix.

References:

1.     Schlaepfer, D.D et al. (2004). Multiple connections link FAK to cell motility and invasion. Curr. Opin. Genet. Dev. 14, 92–110

2.     Sabeh, et al (2004). Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J. Cell Biol. 167, 769–781.

3.     Schmidt, A., et al (1999). Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature 401, 133–141.

4.     Ruest, P.J., et al (2001). Mechanisms of CAS substrate domain tyrosine phosphorylation by FAK and Src. Mol. Cell. Biol. 21, 7641–7652.