TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis

Abstract

Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor b-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)a pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-a treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBa signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBa pathway exhibited increased ROS production and TNF-a-or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.

Transforming growth factor beta-activated kinase 1 (TAK1)-dependent checkpoint in the survival of dendritic cells promotes immune homeostasis and function

“…4A). In addition, production of reactive oxygen species (ROS), which is under the control of TAK1 signaling in other cell types (53), was undisturbed in TAK1-deficient DCs (SI Appendix, Fig. S3).…”

Wound Repair Studies Reveal New Insights to Psoriasis

“…This is especially useful in psoriasis research so that epidermal factors can be isolated and studied alone, without any immune related effects. Using this setup, we found that TAK1 kd OTC epidermis displayed significantly higher ROS levels with an increased incidence of keratinocyte cell death (Lam et al, 2011). This suggests that TAK1 kd keratinocytes succumbed to ROS-induced keratinocyte death even in normal tissue development.…”

“…Interestingly, we have found that the wound expression of transforming growth factor-(TGF-) activated kinase 1 (TAK1), a downstream signaling player of TNF-, coincides with the pattern of ROS production, with peak expression also at 3-7 days post-injury (Lam et al, 2011). Like PPAR / , TAK1 activity is most likely affected by TNF-induction in wounding.…”

“…Using dichlorodihydrofluorescein diacetate (DCF) staining, we assessed levels of intracellular ROS in mouse wounds and found ROS levels in wound epithelial tissue peaking at 3-7 days post-injury (Lam et al, 2011). This ROS up-regulation is likely secondary to the strong pro-inflammatory wound microenvironment, supported by TNF-, which can up-regulate cellular ROS (Kim et al, 2010).…”

Enhancement of wound closure in diabetic mice by ex vivo expanded cord blood CD34+ cells

“…SCF is also found in the dermis during the early phase of normal wound closure but its level declines thereafter [39]. Additionally, SCF has been shown to function in antiapoptosis of keratinocytes during wound closure [40]. It has been reported that human skin keratinocytes and fibroblasts express Flt3-L [41].…”