Netrin-4 regulates angiogenic responses and tumor cell growth.
Netrin-4 is a 628 amino acid basement membrane component that promotes neurite elongation at low concentrations but inhibits neurite extension at high concentrations. There is a growing body of literature suggesting that several molecules, including netrins, are regulators of both neuronal and vascular growth. It is believed that molecules that guide neural growth and development are also involved in regulating morphogenesis of the vascular tree. Further, netrins have recently been implicated in controlling epithelial cell branching morphogenesis in the breast, lung and pancreas. Characterization of purified netrin-4 in in vitro angiogenesis assays demonstrated that netrin-4 markedly inhibits HMVEC migration and tube formation. Moreover, netrin-4 inhibits proliferation of a variety of human tumor cells in vitro. Netrin-4 has only modest effects on proliferation of endothelial and other non-transformed cells. Netrin-4 treatment results in phosphorylation changes of proteins that are known to control cell growth. Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth.
Nacht
Mariana
M
Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701, USA.
St Martin
Thia B
TB
Byrne
Ann
A
Klinger
Katherine W
KW
Teicher
Beverly A
BA
Madden
Stephen L
SL
Jiang
Yide
Y
D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000075385:Netrins; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C498815:NTN4 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins; D012333:RNA, Messenger; D051058:Oncogene Protein v-akt; D048031:JNK Mitogen-Activated Protein Kinases