Exp Neurobiol.  2016 Oct;25(5):269-276. 10.5607/en.2016.25.5.269.

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

• Choi I
• Byun JW
• Park SM
• Jou I
• Joe EH

• KMID: 2354880
• DOI: http://doi.org/10.5607/en.2016.25.5.269

Abstract

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, pT474-FAK 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.

Keyword

Parkinson's disease; LRRK2; FAK; phosphatase; SHP-2

MeSH Terms

Focal Adhesion Protein-Tyrosine Kinases
Glutamic Acid
Parkinson Disease
Phosphoric Monoester Hydrolases
Phosphorylation
Phosphotransferases
Protein Tyrosine Phosphatase, Non-Receptor Type 11*
Threonine
Tyrosine*
Focal Adhesion Protein-Tyrosine Kinases
Glutamic Acid
Phosphoric Monoester Hydrolases
Phosphotransferases
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Threonine
Tyrosine