HGAL, a germinal center specific protein, decreases lymphoma cell motility by modulation of the RhoA signaling pathway.
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.
Jiang
Xiaoyu
X
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
Lu
Xiaoqing
X
McNamara
George
G
Liu
Xiaofei
X
Cubedo
Elena
E
Sarosiek
Kristopher A
KA
Sánchez-García
Isidro
I
Helfman
David M
DM
Lossos
Izidore S
IS
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*
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