CREB Is Activated by the SCF/KIT Axis in a Partially ERK-Dependent Manner and Orchestrates Survival and the Induction of Immediate Early Genes in Human Skin Mast Cells

Abstract

cAMP response element binding protein (CREB) functions as a prototypical stimulus-inducible transcription factor (TF) that initiates multiple cellular changes in response to activation. Despite pronounced expression in mast cells (MCs), CREB function is surprisingly ill-defined in the lineage. Skin MCs (skMCs) are critical effector cells in acute allergic and pseudo-allergic settings, and they contribute to various chronic dermatoses such as urticaria, atopic dermatitis, allergic contact dermatitis, psoriasis, prurigo, rosacea and others. Using MCs of skin origin, we demonstrate herein that CREB is rapidly phosphorylated on serine-133 upon SCF-mediated KIT dimerization. Phosphorylation initiated by the SCF/KIT axis required intrinsic KIT kinase activity and partially depended on ERK1/2, but not on other kinases such as p38, JNK, PI3K or PKA. CREB was constitutively nuclear, where phosphorylation occurred. Interestingly, ERK did not translocate to the nucleus upon SCF activation of skMCs, but a fraction was present in the nucleus at baseline, and phosphorylation was prompted in the cytoplasm and nucleus in situ. CREB was required for SCF-facilitated survival, as demonstrated with the CREB-selective inhibitor 666-15. Knock-down of CREB by RNA interference duplicated CREB’s anti-apoptotic function. On comparison with other modules (PI3K, p38 and MEK/ERK), CREB was equal or more potent at survival promotion. SCF efficiently induces immediate early genes (IEGs) in skMCs (FOS, JUNB and NR4A2). We now demonstrate that CREB is an essential partaker in this induction. Collectively, the ancient TF CREB is a crucial component of skMCs, where it operates as an effector of the SCF/KIT axis, orchestrating IEG induction and lifespan.

An Overview of Growth Factors as the Potential Link between Psoriasis and Metabolic Syndrome

“…Franke et al [ 49 ] showed that the cAMP response element binding protein (CREB) works as a stimulus-inducible transcription factor (TF) that initiates multiple cellular changes in response to activation. Further, CREB is quickly phosphorylated on serine-133 upon stem cell factor (SCF)-mediated KIT dimerization.…”

“…SCF efficiently induces immediate early genes (IEGs) in skin mast cells (skMCs; FOS , JUNB , and NR4A2 ). The TF CREB is an essential crucial intermediary in SCF-triggered KIT activation of human skMCs [ 49 ]; see Table 12 .…”

Discovery and mechanistic study of Imperatorin that inhibits HBsAg expression and cccDNA transcription

“…6 Several studies have reported that the proteins extracellular signal-regulated kinase 1 (ERK1) and ERK2 are required for CREB phosphorylation. Evidence suggests that ERKdependent CREB activation contributes to mast cell hyperplasia, 7 reduces apoptosis in human neuroblastoma, 8 and inhibits oxidative stress to improve the hippocampus-dependent cognitive function. 9 These studies indicate that the ERK/CREB signaling pathway is involved in various biological processes.…”

CREB Is Indispensable to KIT Function in Human Skin Mast Cells—A Positive Feedback Loop between CREB and KIT Orchestrates Skin Mast Cell Fate

“…The most potent modulation is phosphorylation at Ser-133, which enables transactivation through the recruitment of coactivators to the transcriptional machinery [ 10 , 11 , 12 ]. We recently reported that CREB experiences efficient phosphorylation following SCF activation of skin MCs [ 13 ]. Phosphorylation occurs, at least in part, in an ERK-dependent manner, but is independent of other mitogen-activated protein kinases (MAPKs) or Phosphoinositide 3-kinase (PI3K).…”

“…Phosphorylation occurs, at least in part, in an ERK-dependent manner, but is independent of other mitogen-activated protein kinases (MAPKs) or Phosphoinositide 3-kinase (PI3K). CREB has important implications downstream of KIT in MCs, including survival promotion and control of immediate early genes [ 13 ]. Thereby, CREB was identified as a critical downstream effector of the SCF/KIT axis operating in MCs of cutaneous origin.…”