Relevance of IGFBP2 proteolysis in glioma and contribution of the extracellular protease ADAMTS1

// Estefania Martino-Echarri 1 , Ruben Fernandez-Rodriguez 1 , Joan Josep Bech-Serra 2 , Maria del Carmen Plaza-Calonge 1 , Noemi Vidal 3 , Carmen Casal 1 , Nuria Colome 2 , Joan Seoane 2,4 , Francesc Canals 2 and Juan Carlos Rodriguez-Manzaneque 1 1 GENYO. Centre for Genomics and Oncological Research: Pfizer/Universidad de Granada/Junta de Andalucia, Granada, Spain 2 Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Barcelona, Spain 3 Institut de Neuropatologia, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Spain 4 Institucio Catalana de Recerca I Estudis Avancats (ICREA), Barcelona, Spain Correspondence: J.C. Rodriguez-Manzaneque, email: // Keywords : ADAMTS, extracellular proteolysis, glioma, IGFBP2, proteomics Received : February 19, 2014 Accepted : May 24, 2014 Published : May 26, 2014 Abstract Expression of IGFBP2 ( Insulin-like Growth Factor Binding Protein 2 ) has been positively correlated with glioma progression. Although the proteolysis of IGFBP2 has been widely recognized, with consequences as a major modulator of IGFII signaling, the relevance of this post-translational modification has not been well studied in tumors. Using an in vivo proteomic approach by Isotope-Coded Protein Label (ICPL), we identified IGFBP2 as a target of the extracellular protease ADAMTS1 ( A Disintegrin And Metalloproteinase with ThromboSpondin motifs 1 ). Notably, the proteolytic pattern of IGFBP2 was also detected in human glioma culture cells and, more importantly, in all glioma samples evaluated. In addition, high expression of ADAMTS1 correlates with higher levels of cleaved IGFBP2 in glioblastoma multiforme cases. Using gene expression public databases, we confirmed that IGFBP2 is a poor prognosis marker for gliomas, and we also observed an important contribution of ADAMTS1.Finally, we showed the impact of ADAMTS1 on IGFII-mediated IGF1R phosphorylation and cellular migration. Our results support a functional interaction between IGFBP2 and ADAMTS1 and suggest the need to evaluate post-translational modifications of IGFBP2 in glioma, in order to approach new therapies.