HGAL, a lymphoma prognostic biomarker, interacts with the cytoskeleton and mediates the effects of IL-6 on cell migration.
HGAL is a newly identified germinal center (GC)-specific gene whose expression by the tumor cells correlates with a favorable prognosis in patients with diffuse large B-cell and classical Hodgkin lymphomas. The function of HGAL is unknown. Previous studies demonstrated that HGAL is dispensable for GC formation, immunoglobulin gene class-switch recombination, and somatic hypermutation. Herein, we identify a role for HGAL in the regulation of cell motility. We demonstrate that IL-6 induces the phosphorylation of the C-terminal tyrosine residue of the HGAL protein via the Lyn kinase, and promotes its relocalization from the cytoplasm to podosome-like structures. Further, IL-6-induced HGAL phosphorylation increases its interaction with myosin II and is associated with inhibition of cell migration. Knockdown of endogenous HGAL ameliorates IL-6-induced inhibition of cell migration, whereas overexpression of HGAL imparts inhibitory effects of IL-6 on cell migration. Taken together, our results suggest that HGAL is involved in negative regulation of lymphocyte migration, thus constraining lymphocytes to the GC. Inhibition of lymphocyte migration might contribute to the less aggressive clinical behavior of HGAL-expressing lymphomas.
Lu
Xiaoqing
X
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, FL 33136, USA.
Chen
Jun
J
Malumbres
Raquel
R
Cubedo Gil
Elena
E
Helfman
David M
DM
Lossos
Izidore S
IS
D014408:Biomarkers, Tumor; D002465:Cell Movement; D003599:Cytoskeleton / Q000473:pathology*; D018858:Germinal Center; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008214:Lymphocytes; D008223:Lymphoma / Q000473:pathology*; D008840:Microfilament Proteins; D024462:Myosin Type II / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011379:Prognosis; D021381:Protein Transport