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Molecular and Cellular Biology, November 2001, p. 7218-7230, Vol. 21, No. 21
Institute of Signaling, Developmental Biology
and Cancer Research, CNRS UMR 6543-Centre Antoine Lacassagne, 06189 Nice Cedex 2, France
Received 2 March 2001/Returned for modification 19 April
2001/Accepted 6 August 2001
Mouse capillary endothelial cells (1G11 cell line) embedded in type
I collagen gels undergo in vitro angiogenesis. Cells rapidly reorganize
and form capillary-like structures when stimulated with serum.
Transforming growth factor
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.21.7218-7230.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Transforming Growth Factor
1 (TGF-
1) Promotes Endothelial
Cell Survival during In Vitro Angiogenesis via an Autocrine
Mechanism Implicating TGF-
Signaling
1 (TGF-
1) alone can substitute for
serum and induce cell survival and tubular network formation. This
TGF-
1-mediated angiogenic activity depends on phosphatidylinositol 3-kinase (PI3K) and p42/p44 mitogen-activated protein kinase
(MAPK) signaling. We showed that specific inhibitors of either pathway (wortmannin, LY-294002, and PD-98059) all suppressed TGF-
1-induced angiogenesis mainly by compromising cell survival. We established that
TGF-
1 stimulated the expression of TGF-
mRNA and protein, the
tyrosine phosphorylation of a 170-kDa membrane protein representing the
epidermal growth factor (EGF) receptor, and the delayed
activation of PI3K/Akt and p42/p44 MAPK. Moreover, we showed that all
these TGF-
1-mediated signaling events, including tubular network
formation, were suppressed by incubating TGF-
1-stimulated
endothelial cells with a soluble form of an EGF receptor (ErbB-1) or
tyrphostin AG1478, a specific blocker of EGF receptor tyrosine kinase.
Finally, addition of TGF-
alone poorly stimulated angiogenesis;
however, by reducing cell death, it strongly potentiated the
action of TGF-
1. We therefore propose that TGF-
1 promotes
angiogenesis at least in part via the autocrine secretion of TGF-
, a
cell survival growth factor, activating PI3K/Akt and p42/p44 MAPK.
*
Corresponding author. Present address for Francese
Viñals: Facultad de Odontologia, Universitat de Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Spain. E-mail:
fvinals{at}bell.ub.es. Mailing address for Jacques Pouysségur:
Institute of Signaling, Developmental Biology and Cancer Research, CNRS
UMR 6543-Centre Antoine Lacassagne, 33 Av. Valombrose, 06189 Nice Cedex
2, France. Phone: (33) 492 03 1222. Fax: (33) 492 03 1225. E-mail:
pouysseg{at}unice.fr.
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