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Brain‐derived neurotrophic factor, epidermal growth factor, or A‐Raf‐induced growth of HaCaT keratinocytes requires extra‐cellular signal‐regulated protein kinase
Author(s) -
Rössler O. G.,
Thiel G.
Publication year - 2004
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.0906-6705.2004.0212ay.x
Subject(s) - hacat , tropomyosin receptor kinase b , microbiology and biotechnology , tropomyosin receptor kinase a , wortmannin , signal transduction , biology , receptor tyrosine kinase , cancer research , tropomyosin receptor kinase c , mapk/erk pathway , epidermal growth factor , autocrine signalling , neurotrophic factors , neurotrophin , platelet derived growth factor receptor , growth factor , protein kinase b , receptor , cell culture , biochemistry , genetics
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, an indication 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 PD98059, whereas the inhibition of phosphatidylinositol‐3 (PI3) kinase by wortmannin only delayed the proliferative response. The importance of the extracellular signal‐regulated protein kinase (ERK) 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). HaCaT cells expressing ΔA‐Raf:ER proliferated following the activation of mutant A‐Raf protein kinase. Proliferation was completely inhibited by PD98059. Proliferation of HaCaT cells induced by EGF, BDNF, or ΔA‐Raf:ER was also accompanied by the biosynthesis of the transcription factors Egr‐1 and c‐Jun, suggesting that these proteins may be part of the mitogenic signaling cascade.