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Blood Adv. 2019 Aug 13;3(15):2286-2297. doi: 10.1182/bloodadvances.2018016162.

Interplay between HGAL and Grb2 proteins regulates B-cell receptor signaling.

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Division of Oncology-Hematology, Department of Medicine, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL.
Department of Physics, University of Calabria, Rende, Italy.
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL.
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Moleculary Celular del Cáncer, Centro Superior de Investigaciones Científicas/Universidad de Salamanca and Institute of Biomedical Research of Salamanca, Salamanca, Spain; and.
Diabetes Research Institute.
Department of Physiology and Biophysics, and.
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL.


Human germinal center (GC)-associated lymphoma (HGAL) is an adaptor protein expressed in GC B cells. HGAL regulates cell motility and B-cell receptor (BCR) signaling, processes that are central for the successful completion of the GC reaction. Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. The HGAL YEN motif (amino acids 107-109) is similar to the phosphopeptide motif pYXN used as a binding site to the growth factor receptor-bound protein 2 (Grb2). We demonstrate by biochemical and molecular methodologies that HGAL directly interacts with Grb2. Concordantly, microscopy studies demonstrate HGAL-Grb2 colocalization in the membrane central supramolecular activation clusters (cSMAC) following BCR activation. Mutation of the HGAL putative binding site to Grb2 abrogates the interaction between these proteins. Further, this HGAL mutant localizes exclusively in the peripheral SMAC and decreases the rate and intensity of BCR accumulation in the cSMAC. Furthermore, we demonstrate that Grb2, HGAL, and Syk interact in the same complex, but Grb2 does not modulate the effects of HGAL on Syk kinase activity. Overall, the interplay between the HGAL and Grb2 regulates the magnitude of BCR signaling and synapse formation.

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