title: Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor.
abstract: The human cathelicidin antimicrobial protein-18 and its C terminal peptide, LL-37, displays broad antimicrobial activity that is mediated through direct contact with the microbial cell membrane. In addition, recent studies reveal that LL-37 is involved in diverse biological processes such as immunomodulation, apoptosis, angiogenesis and wound healing. An intriguing role for LL-37 in carcinogenesis is also beginning to emerge and the aim of this paper was to explore if and how LL-37 contributes to the signaling involved in tumor development. To this end, we investigated the putative interaction between LL-37 and growth factor receptors known to be involved in tumor growth and progression. Among several receptors tested, LL-37 bound with the highest affinity to insulin-like growth factor 1 receptor (IGF-1R), a receptor that is strongly linked to malignant cellular transformation. Furthermore, this interaction resulted in a dose-dependent phosphorylation and ubiquitination of IGF-1R, with downstream signaling confined to the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-pathway but not affecting phosphatidylinositol 3 kinase/Akt signaling. We found that signaling induced by LL-37 was dependent on the recruitment of β-arrestin to the fully functional IGF-1R and by using mutant receptors we demonstrated that LL-37 signaling is dependent on β-arrestin-1 binding to the C-terminus of IGF-1R. When analyzing the biological consequences of increased ERK activation induced by LL-37, we found that it resulted in enhanced migration and invasion of malignant cells in an IGF-1R/β-arrestin manner, but did not affect cell proliferation. These results indicate that LL-37 may act as a partial agonist for IGF-1R, with subsequent intra-cellular signaling activation driven by the binding of β-arrestin-1 to the IGF-1R. Functional experiments show that LL-37-dependent activation of the IGF-1R signaling resulted in increased migratory and invasive potential of malignant cells.
authors.affiliation: Department of Oncology and Pathology, Cancer Center Karolinska, Stockholm, Sweden. Ada.Girnita@ki.se
authors.forename: A
authors.initials: A
authors.lastname: Girnita
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.forename: A
authors.initials: A
authors.lastname: Grönberg
authors.forename: L
authors.initials: L
authors.lastname: Girnita
authors.forename: M
authors.initials: M
authors.lastname: Ståhle
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism*; D019390:Arrestins / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000819:agonists* / Q000378:metabolism; D054875:Ubiquitination; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D019390:Arrestins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D054804:Cathelicidins; C000605253:ARRB1 protein, human