HGAL localization to cell membrane regulates B-cell receptor signaling.
Human germinal center-associated lymphoma (HGAL) is specifically expressed only in germinal center (GC) B lymphocytes and GC-derived lymphomas. HGAL protein decreases lymphocyte motility by inhibiting the ability of myosin to translocate actin via direct interaction with F-actin and myosin II and by activating RhoA signaling via direct interactions with RhoA-specific guanine nucleotide exchange factors. HGAL protein also regulates B-cell receptor (BCR) signaling by directly binding to and enhancing Syk kinase activity and activation of its downstream effectors. Herein we demonstrate that HGAL protein can be myristoylated and palmitoylated and that these modifications localize HGAL to cellular membrane raft microdomains with distinct consequences for BCR signaling and chemoattractant-induced cell mobility. In BCR signaling, raft localization of HGAL facilitates interaction with Syk and modulation of the BCR activation and signaling, which induces HGAL phosphorylation and redistribution from lipid raft to bulk membrane and cytoplasm, followed by degradation. In contrast, HGAL myristoylation and palmitoylation avert its inhibitory effects on chemoattractant-induced cell motility. These findings further elucidate the growing and complex role of HGAL in B-cell biology and suggest that membrane-bound and cytoplasmic HGAL protein differently regulates distinct biological processes.
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
Xiaoqing
X
Lu
Department of Biochemistry and Molecular Biology.
Renaud
R
Sicard
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center.
Xiaoyu
X
Jiang
Biomedical Engineering Department.
Jessica N
JN
Stockus
Analytical Imaging Core Facility.
George
G
McNamara
Department of Surgery.
Midhat
M
Abdulreda
Department of Physiology and Biophysics, and.
Vincent T
VT
Moy
Department of Biochemistry and Molecular Biology.
Ralf
R
Landgraf
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL.
Izidore S
IS
Lossos
D000199:Actins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002630:Chemotactic Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054878:Lipoylation / Q000235:genetics / Q000276:immunology; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008840:Microfilament Proteins; D024462:Myosin Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059748:Proteolysis; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D000199:Actins; D002630:Chemotactic Factors; C476824:GCSAM protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D024462:Myosin Type II; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein