Mechanical Stretch Stimulates Protein Kinase B/Akt Phosphorylation in Epidermal Cells via Angiotensin II Type 1 Receptor and Epidermal Growth Factor Receptor

Abstract

Mechanical stress is known to modulate fundamental events such as cell life and death. Mechanical stretch in particular has been identified as a positive regulator of proliferation in skin keratinocytes and other cell systems. In the present study it was investigated whether antiapoptotic signaling is also stimulated by mechanical stretch. It was demonstrated that mechanical stretch rapidly induced the phosphorylation of the proto-onco- The application of mechanical forces is a ubiquitous challenge to skin cells. Both differentiation processes and proliferation can be induced by different qualities of mechanical stimulation. In vitro studies have demonstrated that mechanical pressure gives rise to differentiation processes (1, 2), while mechanical stretch supports proliferation in human epidermal cells (3-5). These findings fit the in vivo situation where mechanical pressure provokes horny skin formation, and mechanical stretch, as present in abdominal stretching during pregnancy, induces skin enlargement. Previous in vitro studies on human skin keratinocytes have shown that mechanical stretch induces proliferation-associated signaling cascades of the mitogen-activated protein kinase pathway (4). Particularly the activation of extracellular signal-regulated kinase 1/2 may have functional aspects in stretch-mediated proliferation. As initial events in mechanotransduction, surface receptors of the integrin family are thought to recognize mechanical energy and transduce it into biological signals (6, 7). This assumption is supported by the finding that blocking of ␤ 1 integrins abrogates stretch-induced activation of extracellular signal-regulated kinase 1/2 (4).In addition to increased proliferation, it could be that induction of antiapoptotic signaling pathways may contribute to the increase in cell number in response to mechanical stretch. In particular, the antiapoptotic kinase PKB 1 /Akt is a candidate signaling molecule shown to play a key role in suppression of apoptotic cell death (8, 9). Prototypically, PKB/Akt activation is transduced by cell surface receptors in response to insulin and mitogens such as epidermal growth factor (10 -12). In addition, recent advances have shown that integrins, namely the ␤ 1 and ␤ 4 subsets, stimulate PKB/Akt phosphorylation and therefore may contribute to antiapoptosis (13,14). Proximal from surface receptors, the phosphoinositide 3-OH kinase (PI3K) conveys activation of PKB/Akt via phosphoinositide-dependent kinases. It has been demonstrated that phosphoinositide-dependent kinase-1 phosphorylates PKB/Akt at threonine 308 (15), whereas the mechanism of the serine 473 phosphorylation is still under debate (16,17). Studies regarding the impact of mechanical stimuli on PKB/Akt have been mainly carried out in endothelium-derived cells as hemodynamic changes caused by coronary circulation are known to contribute to pathophysiological processes of the blood vessel system (18 -21). In this context, vascular smooth muscle cells may also respond to mechanical stretch by activation ...

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Stretch-induced activation of the AT 1 receptor protects cells against induced apoptosis involving PKB/Akt signaling (Kippenberger et al, 2005). Mechanical stretch potentiates AngII-induced VSMCs proliferation in spontaneously hypertensive rat through an AT 1 receptor/ EGFR/ERK-dependent pathway.…”

EGFR-Activated Signaling and Actin Remodeling Regulate Cyclic Stretch–Induced NRF2-ARE Activation

“…We focused our studies on EGFR-activated signaling, as it regulates downstream effector pathways (e.g., PI3K and MAP kinases) that activate various transcription factors in response to specific stimuli (26,27). Furthermore, several studies have shown that EGFR acts as a biosensor to transduce signals from mechanical forces in various cell types, including pulmonary epithelial cells (28)(29)(30)(31)(32)(33). To determine whether this receptor-activated signaling modulates CS-induced Nrf2-ARE activation, CS-stimulated ARE-Luc activity was analyzed in the presence or absence of AG1478, a pharmacologic agent that specifically blocks EGFR tyrosine kinase activity.…”

Stretch-Induced Mitogen-Activated Protein Kinase Activation in Lung Fibroblasts Is Independent of Receptor Tyrosine Kinases

“…In a similar study, EGFR was found to be involved in cyclic stretch activation of ERK1/2, although Ras was not implicated (17). The mechanoactivated nature of RTKs has been observed in other tissues as well: Mechanical stretch activates EGFR in keratinocytes (18), stimulates proliferation of vascular smooth muscle cells via the insulin-like growth factor receptor (19), and activates the EGFR (20) and the PDGFR (21,22), with the latter implicated in mechanical strain-induced embryonic stem cell differentiation into vascular smooth muscle cells (23). In this study, we focused on whether the receptor tyrosine kinases EGFR, FGFR, and PDGFR play roles in the proximal mechanotransduction response of human lung fibroblasts to tonic stretch.…”