scholarly journals Induction of MUC2 and MUC5AC Mucins by Factors of the Epidermal Growth Factor (EGF) Family Is Mediated by EGF Receptor/Ras/Raf/Extracellular Signal-regulated Kinase Cascade and Sp1*

2002 ◽  
Vol 277 (35) ◽  
pp. 32258-32267 ◽  
Author(s):  
Michaël Perrais ◽  
Pascal Pigny ◽  
Marie-Christine Copin ◽  
Jean-Pierre Aubert ◽  
Isabelle Van Seuningen
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Kinase Cascade ◽  
Epidermal Growth ◽  
Egf Family

Brain-derived neurotrophic factor-, epidermal growth factor-, or A-Raf-induced growth of HaCaT keratinocytes requires extracellular signal-regulated kinase

2004 ◽  
Vol 286 (5) ◽  
pp. C1118-C1129 ◽  
Author(s):  
Oliver G. Rössler ◽  
Gerald Thiel
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Neurotrophic Factor ◽  
Egf Receptor ◽  
Hacat Cells ◽  
Hacat Keratinocytes ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Epidermal Growth

The epidermal growth factor (EGF) receptor plays an important role in epithelial cells by controlling cell proliferation and survival. Keratinocytes also express another class of receptor tyrosine kinases, the neurotrophin receptors. To analyze the biological role of the neurotrophin brain-derived neurotrophic factor (BDNF) in keratinocytes, we expressed the BDNF receptor TrkB in immortalized human HaCaT keratinocytes. Stimulation of HaCaT-TrkB cells with BDNF induced DNA synthesis and increased mitochondrial reduction capacities, both indications of proliferating cells. An analysis of the signal transduction cascade revealed that the activated TrkB receptor effectively utilized components of the EGF receptor signaling pathway to control cell proliferation. Mitogenic signaling induced by BDNF or EGF was completely abrogated by the MAP kinase kinase inhibitor PD-98059, whereas inhibition of phosphatidylinositol 3-kinase by wortmannin only delayed the proliferative response. The importance of the extracellular signal-regulated kinase signaling pathway for growth of HaCaT keratinocytes was further demonstrated with HaCaT cells engineered to express an inducible A-Raf-estrogen receptor fusion protein (ΔA-Raf:ER). Despite differences in the amplitude and duration of extracellular signal-regulated kinase activation, HaCaT cells expressing ΔA-Raf:ER proliferated after activation of mutant A-Raf protein kinase. Proliferation was completely inhibited by PD-98059. Proliferation of HaCaT cells induced by EGF, BDNF, or ΔA-Raf:ER was also accompanied by biosynthesis of the transcription factors Egr-1 and c-Jun, suggesting that these proteins may be part of the mitogenic signaling cascade.

scholarly journals Role of Epidermal Growth Factor Receptor Signaling in RAS-Driven Melanoma

2005 ◽  
Vol 25 (10) ◽  
pp. 4176-4188 ◽  
Author(s):  
Nabeel Bardeesy ◽  
Minjung Kim ◽  
Jin Xu ◽  
Ryung-Suk Kim ◽  
Qiong Shen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Tumor Model ◽  
Receptor Signaling ◽  
Epidermal Growth ◽  
Egf Family ◽  
Tumor Model System

ABSTRACT The identification of essential genetic elements in pathways governing the maintenance of fully established tumors is critical to the development of effective antioncologic agents. Previous studies revealed an essential role for H-RASV12G in melanoma maintenance in an inducible transgenic model. Here, we sought to define the molecular basis for RAS-dependent tumor maintenance through determination of the H-RASV12G-directed transcriptional program and subsequent functional validation of potential signaling surrogates. The extinction of H-RASV12G expression in established tumors was associated with alterations in the expression of proliferative, antiapoptotic, and angiogenic genes, a profile consistent with the observed phenotype of tumor cell proliferative arrest and death and endothelial cell apoptosis during tumor regression. In particular, these melanomas displayed a prominent RAS-dependent regulation of the epidermal growth factor (EGF) family, leading to establishment of an EGF receptor signaling loop. Genetic complementation and interference studies demonstrated that this signaling loop is essential to H-RASV12G-directed tumorigenesis. Thus, this inducible tumor model system permits the identification and validation of alternative points of therapeutic intervention without neutralization of the primary genetic lesion.

scholarly journals Phosphorylation of Rac1 T108 by Extracellular Signal-Regulated Kinase in Response to Epidermal Growth Factor: a Novel Mechanism To Regulate Rac1 Function

2013 ◽  
Vol 33 (22) ◽  
pp. 4538-4551 ◽  
Author(s):  
Junfeng Tong ◽  
Laiji Li ◽  
Barbara Ballermann ◽  
Zhixiang Wang
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Rho Gtpases ◽  
Fluorescent Protein ◽  
Phosphorylation Site ◽  
Kinase Assay ◽  
Nucleotide Exchange ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Epidermal Growth

Accumulating evidence has implicated Rho GTPases, including Rac1, in many aspects of cancer development. Recent findings suggest that phosphorylation might further contribute to the tight regulation of Rho GTPases. Interestingly, sequence analysis of Rac1 shows that Rac1 T108 within the106PNTP109motif is likely an extracellular signal-regulated kinase (ERK) phosphorylation site and that Rac1 also has an ERK docking site,183KKRKRKCLLL192(D site), at the C terminus. Indeed, we show here that both transfected and endogenous Rac1 interacts with ERK and that this interaction is mediated by its D site. Green fluorescent protein (GFP)-Rac1 is threonine (T) phosphorylated in response to epidermal growth factor (EGF), and EGF-induced Rac1 threonine phosphorylation is dependent on the activation of ERK. Moreover, mutant Rac1 with the mutation of T108 to alanine (A) is not threonine phosphorylated in response to EGF.In vitroERK kinase assay further shows that pure active ERK phosphorylates purified Rac1 but not mutant Rac1 T108A. We also show that Rac1 T108 phosphorylation decreases Rac1 activity, partially due to inhibiting its interaction with phospholipase C-γ1 (PLC-γ1). T108 phosphorylation targets Rac1 to the nucleus, which isolates Rac1 from other guanine nucleotide exchange factors (GEFs) and hinders Rac1's role in cell migration. We conclude that Rac1 T108 is phosphorylated by ERK in response to EGF, which plays an important role in regulating Rac1.

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