HGAL, a germinal center specific protein, decreases lymphoma cell motility by modulation of the RhoA signaling pathway

Author:

Jiang Xiaoyu1,Lu Xiaoqing1,McNamara George12,Liu Xiaofei3,Cubedo Elena1,Sarosiek Kristopher A.1,Sánchez-García Isidro4,Helfman David M.5,Lossos Izidore S.16

Affiliation:

1. Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL;

2. Analytical Imaging Core Facility (AICF), University of Miami, Miami, FL;

3. Department of Cell Biology and Anatomy, University of Miami, Miami, FL;

4. Instituto de Biología Molecular y Celular del Cáncer, Universidad de Salamanca, Salamanca, Spain;

5. Department of Biological Sciences and Graduate School of Nanoscience and Technology (WCU), Korean Advanced Institute of Science and Technology, Daejon, Korea; and

6. Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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