DLG1/SAP97 modulates transforming growth factor α bioavailability

TGF alpha and its receptor EGFR participate in the development of a wide range of tumors including gliomas, the main adult primary brain tumors. TGF alpha soluble form results from the cleavage by the metalloprotease TACE/ADAM17 of the extracellular part of its transmembrane precursor, pro-TGF alpha. To gain insights into the mechanisms underlying TCF alpha bioavailability, a yeast two-hybrid screen was performed to identify proteins interacting with pro-TGF alpha intracellular domain (ICD). DLG1/SAP97 (Discs Large Gene I or Synapse Associated Protein 97) was found to interact with both pro-TGF alpha and TACE ICDs through distinct PDZ domains. An in vivo pro-TGF alpha-DLG1-TACE complex was detected in U251 glioma cells and in gliomas-derived tumor initiating cells. Interaction between DLG1 and TACE diminished in response to stimulations promoting proTGF alpha shedding. Manipulation of DLG1 levels revealed dual actions of DLG1 on pro-TGF alpha shedding, favoring approximation of pro-TGFa and TACE, while limiting TACE full shedding activity. These results show that DLG1 participates in the control of TGF alpha bioavailability through its dynamic interaction with the growth factor precursor and TACE. (c) 2008 Elsevier B.V. All rights reserved.