title: Inhibition of Phosphatase Activity Follows Decline in Sulfatase Activity and Leads to Transcriptional Effects through Sustained Phosphorylation of Transcription Factor MITF.
abstract: Arylsulfatase B (B-acetylgalactosamine 4-sulfatase; ARSB) is the enzyme that removes 4-sulfate groups from the non-reducing end of the glycosaminoglycans chondroitin 4-sulfate and dermatan sulfate. Decline in ARSB has been shown in malignant prostate, colonic, and mammary cells and tissues, and decline in ARSB leads to transcriptional events mediated by galectin-3 with AP-1 and Sp1. Increased mRNA expression of GPNMB (transmembrane glycoprotein NMB) in HepG2 cells and in hepatic tissue from ARSB-deficient mice followed decline in expression of ARSB and was mediated by the microphthalmia-associated transcription factor (MITF), but was unaffected by silencing galectin-3. Since GPNMB is increased in multiple malignancies, studies were performed to determine how decline in ARSB increased GPNMB expression. The mechanism by which decline in ARSB increased nuclear phospho-MITF was due to reduced activity of SHP2, a protein tyrosine phosphatase with Src homology (SH2) domains that regulates multiple cellular processes. SHP2 activity declined due to increased binding with chondroitin 4-sulfate when ARSB was reduced. When SHP2 activity was inhibited, phosphorylations of p38 mitogen-associated phosphokinase (MAPK) and of MITF increased, leading to GPNMB promoter activation. A dominant negative SHP2 construct, the SHP2 inhibitor PHSP1, and silencing of ARSB increased phospho-p38, nuclear MITF, and GPNMB. In contrast, constitutively active SHP2 and overexpression of ARSB inhibited GPNMB expression. The interaction between chondroitin 4-sulfate and SHP2 is a novel intersection between sulfation and phosphorylation, by which decline in ARSB and increased chondroitin 4-sulfation can inhibit SHP2, thereby regulating downstream tyrosine phosphorylations by sustained phosphorylations with associated activation of signaling and transcriptional events.
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America.|Jesse Brown VA Medical Center, Chicago, Illinois, 60612, United States of America.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America.|Jesse Brown VA Medical Center, Chicago, Illinois, 60612, United States of America.
authors.forename: Leo
authors.initials: L
authors.lastname: Feferman
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America.|Jesse Brown VA Medical Center, Chicago, Illinois, 60612, United States of America.
authors.forename: Joanne K
authors.initials: JK
authors.lastname: Tobacman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000378:metabolism; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018909:src Homology Domains
chemical_list: C503042:GPNMB protein, human; D037502:Galectin 3; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D002809:Chondroitin Sulfates; D048051:p38 Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D020051:N-Acetylgalactosamine-4-Sulfatase