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This version published online on June 30, 2005
Endocrinology, doi:10.1210/en.2005-0467
A more recent version of this article appeared on October 1, 2005
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Submitted on April 20, 2005
Accepted on June 23, 2005

IGFBP-2 BINDING TO EXTRACELLULAR MATRIX PLAYS A CRITICAL ROLE IN NEUROBLASTOMA CELL PROLIFERATION, MIGRATION AND INVASION

V C Russo*, B S Schütt, E Andaloro, S I Ymer, A Hoeflich, M B Ranke, L A Bach, and G A Werther

Murdoch Childrens Research Institute, Centre for Hormone Research; Dept. of Paediatrics University of Melbourne, Parkville 3052, Victoria, Australia.; University Children's Hospital, 72076 Tübingen, Germany; Institute of Animal breeding, Ludwig-Maximilian University, Munich, Germany; Dept. of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia

* To whom correspondence should be addressed. E-mail: vince.russo{at}mcri.edu.au.

IGFBPs modulate IGF cellular bio-availability and may directly regulate tumor growth and invasion. We have previously shown that IGFBP-2 binds and localizes IGF-I to the pericellular matrix, and have provided some evidence suggesting that the heparin binding domain (HBD) or the RGD integrin binding motif may be involved in these interactions. However the precise mechanisms involved remain to be elucidated. We therefore mutated the HBD or the RGD sequence of IGFBP-2 and investigated consequent effects on ECM binding, IGF-induced proliferation and migration of neuroblastoma cells. IGFBP-2 and its RGE mutant similarly bound ECM components, while binding of mutant HBD-IGFBP-2 to each of the ECM substrates was markedly reduced by 70-80% (P < 0.05). IGF-I (100ng/ml) increased incorporation of 3H-thymidine in neuroblastoma SK-N-SHEP cells by ~30%, an effect blunted by exogenously added native or either mutant IGFBP-2. Over-expression of IGFBP-2 and its RGE mutant potently promoted SHEP cell proliferation (5-fold), while SHEP cell proliferation was negligible when HBD-IGFBP-2 was over-expressed. Addition or over-expression of IGFBP-2 and its RGE mutant potently (P < 0.05) enhanced SHEP cell migration/invasion through the ECM. However, over-expression of the HBD-IGFBP-2 mutant potently inhibited (50-60%) SHEP cell invasion through ECM. Thus IGFBP-2, which binds to the ECM, enhances proliferation and metastatic behavior of neuroblastoma cells, functions that directly or indirectly use the HBD but not the integrin binding sequence. Our novel findings thus point to a key role for the HBD of IGFBP-2 in the control and regulation of neuroblastoma growth and invasion.
Key words: Neuroblastoma • adhesion • invasion • IGFBP-2 • heparin binding domain • integrin binding domain • mutagenesis • proteoglycans • extracellular matrix proteins • IGF-I




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