title: A novel interaction between calcium-modulating cyclophilin ligand and Basigin regulates calcium signaling and matrix metalloproteinase activities in human melanoma cells.
abstract: Intracellular free calcium is a ubiquitous second messenger regulating a multitude of normal and pathogenic cellular responses, including the development of melanoma. Upstream signaling pathways regulating the intracellular free calcium concentration ([Ca2+]i) may therefore have a significant impact on melanoma growth and metastasis. In this study, we demonstrate that the endoplasmic reticulum (ER)-associated protein calcium-modulating cyclophilin ligand (CAML) is bound to Basigin, a widely expressed integral plasma membrane glycoprotein and extracellular matrix metalloproteinase inducer (EMMPRIN, or CD147) implicated in melanoma proliferation, invasiveness, and metastasis. This interaction between CAML and Basigin was first identified using yeast two-hybrid screening and further confirmed by co-immunoprecipitation. In human A375 melanoma cells, CAML and Basigin were co-localized to the ER. Knockdown of Basigin in melanoma cells by siRNA significantly decreased resting [Ca2+]i and the [Ca2+]i increase induced by the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin (TG), indicating that the interaction between CAML and Basigin regulates ER-dependent [Ca2+]i signaling. Meanwhile upregulating the [Ca2+]i either by TG or phorbol myristate acetate (PMA) could stimulate the production of MMP-9 in A375 cells with the expression of Basigin. Our study has revealed a previously uncharacterized [Ca2+]i signaling pathway that may control melanoma invasion, and metastasis. Disruption of this pathway may be a novel therapeutic strategy for melanoma treatment.
authors.affiliation: Department of Dermatology, XiangYa Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Long
authors.forename: Juan
authors.initials: J
authors.lastname: Su
authors.forename: Wen
authors.initials: W
authors.lastname: Tang
authors.forename: Zhongling
authors.initials: Z
authors.lastname: Luo
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Zhaoqian
authors.initials: Z
authors.lastname: Liu
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Qi
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zeng
authors.forename: Jianglin
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D051926:Basigin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C089404:CAMLG protein, human; D051926:Basigin; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D002118:Calcium
keywords: Basigin; CAML; Calcium; D105–199; D207–230; D207–269; D231–269; D34–89; EMMPRIN; FL; IgG; MMP; Melanoma; NF-AT; OPNG; PMA; SERCA; TACI; TG; WCL; calcium modulating cyclophilin ligand; co-IP; co-immunoprecipitation; deletion of the cytoplasmic domain; deletion of the first IgG; deletion of the second IgG; deletion of the transmembrane and cytoplasmic domain; deletion of the transmembrane domain; extracellular matrix metalloproteinase inducer; full length; immunoglobulin; mIgG; matrix metalloproteinase; mouse IgG; ortho-nitrophenyl-β-D-galactopyranoside; phorbol myristate acetate; sarco/endoplasmic reticulum Ca(2+)-ATPase; si-RNA; small interfering RNA; thapsigargin; the nuclear factor of activated T cells transcription factor; transmembrane activator and CAML-interactor; whole cell lysate