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Heparin‐binding epidermal growth factor‐like growth factor stimulates cell proliferation in cerebral cortical cultures through phosphatidylinositol 3′‐kinase and mitogen‐activated protein kinase
Author(s) -
Jin Kunlin,
Ou Mao Xiao,
Del Rio Guerra Gabriel,
Jin Lan,
Greenberg David A.
Publication year - 2005
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20510
Subject(s) - wortmannin , epidermal growth factor , mapk/erk pathway , heparin binding egf like growth factor , protein kinase b , cell growth , microbiology and biotechnology , biology , ly294002 , growth factor , kinase , protein kinase a , signal transduction , chemistry , biochemistry , receptor
Heparin‐binding epidermal growth factor (EGF)‐like growth factor (HB‐EGF) stimulates cell proliferation in the adult mammalian brain, but the mechanism involved is unknown. To address this issue we treated mouse brain cerebral cortical cultures enriched in neuronal precursors with full‐length HB‐EGF, its HB or EGF‐like domain alone, or both domains in combination. Labeling of cultures with bromodeoxyuridine (BrdU), a marker of cell proliferation, was increased ∼10% by the HB domain and ∼20% by the EGF‐like domain, and the effects of the two domains were additive. Full‐length HB‐EGF was most effective (∼50% increase) in stimulating BrdU incorporation. Preincubation with heparinase III or with Na‐chlorate abolished cell proliferation induced by HB‐EGF, consistent with dependence on cell‐surface heparan sulfate proteoglycans. The effect of HB‐EGF was also blocked by the EGF receptor (EGFR/ErbB1) inhibitors PD153035 and PD158780, implicating EGFR in HB‐EGF‐induced cell proliferation. The phosphatidylinositol 3′‐kinase (PI3K) inhibitors LY294002 and wortmannin, and the MAPK/extracellular signal‐regulated kinase (ERK) kinase (MEK) inhibitors U0126 and PD98059, reduced HB‐EGF‐induced BrdU incorporation into cultures, and HB‐EGF enhanced phosphorylation of Akt and ERK, implying a role for PI3K/Akt and MEK/ERK signaling in HB‐EGF‐stimulated cell proliferation. These findings help to clarify the molecular mechanisms through which HB‐EGF operates. © 2005 Wiley‐Liss, Inc.