title: Extracellular calumenin suppresses ERK1/2 signaling and cell migration by protecting fibulin-1 from MMP-13-mediated proteolysis.
abstract: Extracellular proteins are vital for cell activities, such as cell migration. Calumenin is highly conserved among eukaryotes, but its functions are largely unclear. Here, we identify extracellular calumenin as a suppressor of cell migration and tumor metastasis. Calumenin binds to and stabilizes fibulin-1, leading to inactivation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling. We further identify the minimal functional domain of calumenin (amino acids 74-138 and 214-280). Depletion of calumenin induces fibulin-1- and phospho-ERK1/2 (pERK1/2)-dependent promotion of cell migration. Consistently, in hepatocellular and pancreatic carcinoma, both calumenin and fibulin-1 are downregulated. Furthermore, we show that matrix metalloproteinase-13 (MMP-13) proteolyzes fibulin-1 and that calumenin protects fibulin-1 from cleavage by MMP-13. Calumenin, together with fibulin-1, also interacts with fibronectin and depends on both syndecan-4 and α5β1-integrin to suppress ERK1/2 signaling and inhibit cell migration. Thus, extracellular calumenin regulates fibulin-1 to have crucial roles in ERK1/2 signaling and cell migration.
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: P
authors.initials: P
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: H
authors.initials: H
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.affiliation: 1] State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China [2] Center for Quantitative Biology, Peking University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Bio-Membrane and Membrane Bio-Engineering, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, Department of Cell Biology and Genetics, College of Life Sciences, Peking University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Teng
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics*; D015536:Down-Regulation; D005110:Extracellular Space; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059748:Proteolysis; D014407:Tumor Cells, Cultured
chemical_list: D002135:Calcium-Binding Proteins; C107182:Calu protein, mouse; C060820:fibulin; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse