FAK, SHP2 及JNK 在足體環形成過程中的角色

Abstract

Podosomes are actin-based and phosphorylated protein-enriched structures that promote invasive cell motility and extracellular matrix degradation. They are often found to assemble into large rosette-like structures called podosome rosettes in some types of cells. However, the mechanism of this assembly remains obscure. In this dissertation, I endeavor to examine the effect of focal adhesion kinase (FAK), c-Jun N-terminal kinase (JNK), and tyrosine phosphatase Src homolog domain-containing phosphatase 2 (SHP2) on podosome rosette formation. First, I identified FAK as a key molecule necessary for podosome rosette assembly. The increase in tyrosine phosphorylation of p130Cas and suppression of Rho signaling by FAK were found to be important for FAK to induce the assembly of podosome rosettes. In addition, I found that suppression of vimentin intermediate filaments by FAK facilitates the assembly of podosome rosettes. Second, I found SHP2 suppressed podosome rosette formation in Src-transformed fibroblasts. Moreover, SHP2 selectively suppressed the tyrosine phosphorylation of podosomal protein Tks5, a scaffolding protein, and activated ROCK II through the dephosphorylation of Y722 of ROCK II to repress podosome rosette formation. Third, I demonstrated that JNK is important for podosome rosette formation in Src-transformed fibroblasts and lung adenocarcinoma CL1-5 cells. Moesin, a member of the ERM (ezrin, radixin, and moesin) protein family, was identified as a substrate of JNK. I show that the phosphorylation of moesin at Thr558 by JNK is important for podosome rosette formation. Taken together, my PhD study discovers that FAK and JNK promote podosome rosette formation, but SHP2 is a negative regulator for the process.