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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.
J Neurosci Res. 2005 Aug 15; 81(4):497-505.JN

Abstract

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 approximately 10% by the HB domain and approximately 20% by the EGF-like domain, and the effects of the two domains were additive. Full-length HB-EGF was most effective (approximately 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.

Authors+Show Affiliations

Buck Institute for Age Research, Novato, California.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15952178

Citation

Jin, Kunlin, et al. "Heparin-binding Epidermal Growth Factor-like Growth Factor Stimulates Cell Proliferation in Cerebral Cortical Cultures Through Phosphatidylinositol 3'-kinase and Mitogen-activated Protein Kinase." Journal of Neuroscience Research, vol. 81, no. 4, 2005, pp. 497-505.
Jin K, Mao XO, Del Rio Guerra G, et al. Heparin-binding epidermal growth factor-like growth factor stimulates cell proliferation in cerebral cortical cultures through phosphatidylinositol 3'-kinase and mitogen-activated protein kinase. J Neurosci Res. 2005;81(4):497-505.
Jin, K., Mao, X. O., Del Rio Guerra, G., Jin, L., & Greenberg, D. A. (2005). Heparin-binding epidermal growth factor-like growth factor stimulates cell proliferation in cerebral cortical cultures through phosphatidylinositol 3'-kinase and mitogen-activated protein kinase. Journal of Neuroscience Research, 81(4), 497-505.
Jin K, et al. Heparin-binding Epidermal Growth Factor-like Growth Factor Stimulates Cell Proliferation in Cerebral Cortical Cultures Through Phosphatidylinositol 3'-kinase and Mitogen-activated Protein Kinase. J Neurosci Res. 2005 Aug 15;81(4):497-505. PubMed PMID: 15952178.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Heparin-binding epidermal growth factor-like growth factor stimulates cell proliferation in cerebral cortical cultures through phosphatidylinositol 3'-kinase and mitogen-activated protein kinase. AU - Jin,Kunlin, AU - Mao,Xiao Ou, AU - Del Rio Guerra,Gabriel, AU - Jin,Lan, AU - Greenberg,David A, PY - 2005/6/14/pubmed PY - 2005/10/21/medline PY - 2005/6/14/entrez SP - 497 EP - 505 JF - Journal of neuroscience research JO - J. Neurosci. Res. VL - 81 IS - 4 N2 - 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 approximately 10% by the HB domain and approximately 20% by the EGF-like domain, and the effects of the two domains were additive. Full-length HB-EGF was most effective (approximately 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. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/15952178/Heparin_binding_epidermal_growth_factor_like_growth_factor_stimulates_cell_proliferation_in_cerebral_cortical_cultures_through_phosphatidylinositol_3'_kinase_and_mitogen_activated_protein_kinase_ L2 - https://doi.org/10.1002/jnr.20510 DB - PRIME DP - Unbound Medicine ER -