HGAL inhibits lymphoma dissemination by interacting with multiple cytoskeletal proteins

Abstract

Human Germinal Center Associated Lymphoma (HGAL) is an adaptor protein specifically expressed in germinal center lymphocytes. High expression of HGAL is a predictor of prolonged survival of Diffuse Large B-Cell (DLBCL) and classical Hodgkin lymphomas. Furthermore, HGAL expression is associated with early stage DLBCL, thus potentially limiting lymphoma dissemination. In our previous studies, we demonstrated that HGAL regulates B-cell receptor signaling and cell motility in vitro and deciphered some molecular mechanisms underlying these effects. Herein, by using novel animal models for in vivo DLBCL dispersion, we demonstrate that HGAL decreases lymphoma dissemination and prolongs survival. Further, by using an unbiased proteomic approach we demonstrate that HGAL may interact with multiple cytoskeletal proteins whereby implicating a multiplicity of effects in regulating lymphoma motility and spread. Specifically, we show that HGAL interacts with tubulin and this interaction may also contribute to HGAL effects on cell motility. These findings recapitulate previous observations in humans, establish the role of HGAL in lymphoma in vivo dissemination, and explain improved survival of patients with HGAL expressing lymphomas.

Role of an adaptor protein human germinal center-associated lymphoma (HGAL) in cell signaling and lymphomagenesis

“…This leads to the prolongation of the myosin-actin interaction, contributing to a decreased ability of myosin to translocate actin. An HGAL-induced decrease in actin filament sliding velocity, as demonstrated by the in vitro motility assays, supports this idea [104]. Alternatively, but not mutually exclusive, HGAL binding to myosin and/or actin may serve as a 'load' that resists actin filament motion, hence leading to the same effects [104].…”

“…The mechanisms regulating the motility of GC lymphocytes and lymphoma cells are only partially elucidated [98][99][100][101][102]. It was demonstrated that HGAL, in addition to regulating BCR signaling [55,57,58], also decreases spontaneous and stimuli induced [e.g., stromal cell derived factor 1 (SDF-1), IL-6, fibronectin] motility by several molecular mechanisms [56,[103][104][105].…”

“…Hydrolysis of the ATP by myosin releases free energy to produce a mechanical force for directed actin-based movement [106,107]. HGAL interacts directly and independently with both actin and myosin [103,104]. HGAL protein interacts with two myosin regions: the head (S1) and tail [104].…”

“…HGAL interacts directly and independently with both actin and myosin [103,104]. HGAL protein interacts with two myosin regions: the head (S1) and tail [104]. Although the tail domain generally mediates interaction with the 'cargo' and/or other myosin molecules, the head domain is also involved in binding to F-actin, which is coupled to steps in the hydrolysis of ATP and the transduction of free energy into directed actin-based movement.…”

“…Although the tail domain generally mediates interaction with the 'cargo' and/or other myosin molecules, the head domain is also involved in binding to F-actin, which is coupled to steps in the hydrolysis of ATP and the transduction of free energy into directed actin-based movement. HGAL is not affecting the actomyosin adenosine triphosphatase (ATPase) activity, although it increases the strength of actin-myosin binding [104]. This leads to the prolongation of the myosin-actin interaction, contributing to a decreased ability of myosin to translocate actin.…”