title: LGALS3BP, lectin galactoside-binding soluble 3 binding protein, promotes oncogenic cellular events impeded by antibody intervention.
abstract: The extracellular matrix protein lectin galactoside-binding soluble 3 binding protein (LGALS3BP) constitutes a negative prognostic marker of cancer onset and progression with increasing value in clinical application. Since its discovery, however, although the glycoprotein has been implicated in a growing number of disease-related processes, its actual role and mechanism of action have remained ambiguous, thus hindering opportunities for therapeutic development. In this study, we have determined that LGALS3BP constitutes a novel ligand for integrins α1β1, α5β1, αvβ1 and α6β1 and have identified that these newly established partnerships at the membrane level are responsible for exerting the molecule's involvement in cancer through manipulation of multiple canonical 'outside-in' integrin signalling events. We demonstrate that LGALS3BP-mediated integrin activation results into signal transmission via Akt, JNK and the Ras cascade via the Raf-ERK axis while p38 activity is kept at baseline levels. Transient cellular adherence to LGALS3BP favours survival and proliferation signalling while apoptosis is kept at bay. Sustained cellular exposure to LGALS3BP significantly supports viability, motility and migration. Importantly, an anti-LGALS3BP antibody, SP2 is capable of impeding these newly defined LGALS3BP-driven processes without, however, compromising cell viability. These novel findings reveal the mechanism of action of LGALS3BP during cellular adherence and warrant its further validation as a potential pharmacological target for anticancer therapies.
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Stampolidis
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ullrich
authors.affiliation: MediaPharma s.r.l., Chieti, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iacobelli
mesh_terms: D000906:Antibodies / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D011485:Protein Binding; D015398:Signal Transduction; D016326:Extracellular Matrix Proteins
chemical_list: D000906:Antibodies; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D006023:Glycoproteins; D016023:Integrins; D008024:Ligands; C081856:LGALS3BP protein, human; D016326:Extracellular Matrix Proteins