LRRK2 Inhibits FAK Activity by Promoting FERM-mediated Autoinhibition of FAK and Recruiting the Tyrosine Phosphatase, SHP-2

被引:5
|
作者
Choi, Insup [1 ,2 ,3 ,4 ]
Byun, Ji-Won [1 ]
Park, Sang Myun [1 ,2 ,4 ]
Jou, Ilo [1 ,2 ,4 ]
Joe, Eun-Hye [1 ,2 ,3 ,4 ]
机构
[1] Ajou Univ, Sch Med, Dept Biomed Sci, Neurosci Grad Program, Suwon 16499, South Korea
[2] Ajou Univ, Sch Med, Dept Pharmacol, Suwon 16499, South Korea
[3] Ajou Univ, Sch Med, Dept Brain Sci, Suwon 16499, South Korea
[4] Ajou Univ, Sch Med, Chron Inflammatory Dis Res Ctr, Suwon 16499, South Korea
关键词
Parkinson's disease; LRRK2; FAK; phosphatase; SHP-2; FOCAL ADHESION KINASE; ENDOTHELIAL GROWTH-FACTOR; PARKINSONS-DISEASE; CELL-PROLIFERATION; PHOSPHORYLATION; DOMAIN; BRAIN; DEPHOSPHORYLATION; G2019S; AUTOPHOSPHORYLATION;
D O I
10.5607/en.2016.25.5.269
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Mutation of leucine-rich repeat kinase 2 (LRRK2) causes an autosomal dominant and late-onset familial Parkinson's disease (PD). Recently, we reported that LRRK2 directly binds to and phosphorylates the threonine 474 (T474)-containing Thr-X-Arg(Lys) (TXR) motif of focal adhesion kinase (FAK), thereby inhibiting the phosphorylation of FAK at tyrosine (Y) 397 residue (pY397-FAK), which is a marker of its activation. Mechanistically, however, it remained unclear how T474-FAK phosphorylation suppressed FAK activation. Here, we report that T474-FAK phosphorylation could inhibit FAK activation via at least two different mechanisms. First, T474 phosphorylation appears to induce a conformational change of FAK, enabling its N-terminal FERM domain to autoinhibit Y397 phosphorylation. This is supported by the observation that the levels of pY397-FAK were increased by deletion of the FERM domain and/or mutation of the FERM domain to prevent its interaction with the kinase domain of FAK. Second, pT474FAK appears to recruit SHP-2, which is a phosphatase responsible for dephosphorylating pY397-FAK. We found that mutation of T474 into glutamate (T474E-FAK) to mimic phosphorylation induced more strong interaction with SHP-2 than WT-FAK, and that pharmacological inhibition of SHP-2 with NSC-87877 rescued the level of pY397 in HEK293T cells. These results collectively show that LRRK2 suppresses FAK activation through diverse mechanisms that include the promotion of autoinhibition and/or the recruitment of phosphatases, such as SHP-2.
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页码:269 / 276
页数:8
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