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Mechanistic Target of Rapamycin Complex 1 (mTORC1) and mTORC2 as Key Signaling
Intermediates in Mesenchymal Cell Activation
#MMPMID26755732
Walker NM
; Belloli EA
; Stuckey L
; Chan KM
; Lin J
; Lynch W
; Chang A
; Mazzoni SM
; Fingar DC
; Lama VN
J Biol Chem
2016[Mar]; 291
(12
): 6262-71
PMID26755732
show ga
Fibrotic diseases display mesenchymal cell (MC) activation with pathologic
deposition of matrix proteins such as collagen. Here we investigate the role of
mTOR complex 1 (mTORC1) and mTORC2 in regulating MC collagen expression, a
hallmark of fibrotic disease. Relative to normal MCs (non-Fib MCs), MCs derived
from fibrotic human lung allografts (Fib-MCs) demonstrated increased
phosphoinositide-3kinase (PI3K) dependent activation of both mTORC1 and mTORC2,
as measured by increased phosphorylation of S6K1 and 4E-BP1 (mTORC1 substrates)
and AKT (an mTORC2 substrate). Dual ATP-competitive TORC1/2 inhibitor AZD8055, in
contrast to allosteric mTORC1-specific inhibitor rapamycin, strongly inhibited
4E-BP1 phosphorylation and collagen I expression in Fib-MCs. In non-Fib MCs,
increased mTORC1 signaling was shown to augment collagen I expression.
mTORC1/4E-BP1 pathway was identified as an important driver of collagen I
expression in Fib-MCs in experiments utilizing raptor gene silencing and
overexpression of dominant-inhibitory 4E-BP1. Furthermore, siRNA-mediated
knockdown of rictor, an mTORC2 partner protein, reduced mTORC1 substrate
phosphorylation and collagen expression in Fib-, but not non-Fib MCs, revealing a
dependence of mTORC1 signaling on mTORC2 function in activated MCs. Together
these studies suggest a novel paradigm where fibrotic activation in MCs increases
PI3K dependent mTORC1 and mTORC2 signaling and leads to increased collagen I
expression via the mTORC1-dependent 4E-BP1/eIF4E pathway. These data provide
rationale for targeting specific components of mTORC pathways in fibrotic states
and underscore the need to further delineate mTORC2 signaling in activated cell
states.
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