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The mTOR-FAK mechanotransduction signaling axis for focal adhesion maturation and
cell proliferation
#MMPMID28469768
Lee FY
; Zhen YY
; Yuen CM
; Fan R
; Chen YT
; Sheu JJ
; Chen YL
; Wang CJ
; Sun CK
; Yip HK
Am J Transl Res
2017[]; 9
(4
): 1603-1617
PMID28469768
show ga
BACKGROUND: Mechanotransduction (MTD) is an important physiopathological
signalling pathway associated with cardiovascular disease such as hypertension.
Phosphorylation of focal adhesion kinase (FAK) is a MTD-sensing protein. This
study tested the hypothesis that mTOR-FAK MTD signaling axis was crucial for
focal adhesion (FA) maturation and cell proliferation. METHODS: Shock-wave was
adopted as a tool for MTD and mTOR-FAK signaling. RESULTS: After demonstrating a
failure in FAK phosphorylation after microfilament depolymerization, we attempted
to identify the upstream regulator out of three kinases known to be activated in
pressure-stimulated MTD [i.e., GSK-3?, Akt, and mTORC1 (mammalian target of
rapamycin complex 1)]. Of the three specific inhibitors, only rapamycin, an
inhibitor of mTORC1, was found to inhibit FAK phosphorylation, suggesting that
mTORC1 is the upstream regulator in shock-wave-elicited FAK phosphorylation.
Moreover, mTOR and its readout protein S6K were found to be activated by
shock-wave stimulation. On the other hand, microscopic examination revealed not
only MTD-induced increase in the number of actin stress fibers, but also
alternative subcellular localization of mTORC1 as vesicle-like inclusions on
microfilaments. Besides, rapamycin was found to destruct the granular pattern of
mTORC1, while dissociation between F-actin and mTORC1 was noted after
cytochalasin D administration. Since mTORC1 and FAK are essential for cell
proliferation, we performed proliferation assay for mesenchymal stem cell (MSC)
with and without shock-wave administration/rapamycin treatment/FAK depletion. The
results demonstrated significant enhancement of cell proliferation after
shock-wave stimulation but remarkable suppression after rapamycin and siFAK
treatment. CONCLUSION: Our findings suggest not only a co-ordinated regulation of
FAK phosphorylation by mTORC1 and microfilaments, but also the participation of
mTORC1-FAK signalling in MSC proliferation.
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