title: HGAL, a germinal center specific protein, decreases lymphoma cell motility by modulation of the RhoA signaling pathway.
abstract: HGAL is a germinal center (GC)-specific gene that negatively regulates lymphocyte motility and whose expression predicts improved survival of patients with diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). We demonstrate that HGAL serves as a regulator of the RhoA signaling pathway. HGAL enhances activation of RhoA and its down-stream effectors by a novel mechanism - direct binding to the catalytic DH-domain of the RhoA-specific guanine nucleotide exchange factors (RhoGEFs) PDZ-RhoGEF and LARG that stimulate the GDP-GTP exchange rate of RhoA. We delineate the structural domain of HGAL that mediates its interaction with the PDZ-RhoGEF protein. These observations reveal a novel molecular mechanism underlying the inhibitory effects of GC-specific HGAL protein on the motility of GC-derived lymphoma cells. This mechanism may underlie the limited dissemination and better outcome of patients with HGAL-expressing DLBCL and cHL.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Lu
authors.forename: George
authors.initials: G
authors.lastname: McNamara
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liu
authors.forename: Elena
authors.initials: E
authors.lastname: Cubedo
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
authors.forename: David M
authors.initials: DM
authors.lastname: Helfman
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D001665:Binding Sites; D002465:Cell Movement; D018858:Germinal Center / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008223:Lymphoma / Q000473:pathology*; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000502:physiology*; D011485:Protein Binding; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C476824:GCSAM protein, human; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D020742:rhoA GTP-Binding Protein