Activation of Epstein–Barr virus/C3d receptor (gp140, CR2, CD21) on human B lymphoma cell surface triggers Cbl tyrosine phosphorylation, its association with p85 subunit, Crk-L and Syk and its dissociation with Vav

International audienceIt is well established that CD21 activation on human B cell surface triggers B cell proliferation. We previously demonstrated that CD21 activation also triggers tyrosine phosphorylation of two components, p95 and p120, both interacting with SH2 domains of the p85 subunit of PI 3-kinase. We successively identified p95 as the nucleolin and the first signal transduction pathway specifically triggered by CD21 activation, i.e.: pp60Src activation, tyrosine phosphorylation of p95 nucleolin, its interaction with SH2 domains of p85 subunit and PI 3-kinase activation, followed by AKT-GSK-3 activations. We herein identified the p120 component as the protooncoprotein Cbl and the first steps associated to its activation. First, CD21 activation triggered Cbl tyrosine phosphorylation, which required c-Src kinase but not PI 3-kinase or Syk kinase activities. Involvement of Src kinase in this step was supported by inhibition of Cbl phosphorylation and its interactions with other components when cells were either preincubated with specific Src inhibitor or transfected with dominant-negative c-Src form. Second, once tyrosine phosphorylated, Cbl interacts with SH2 domains of p85 subunit, SH2 domains of Crk-L and with tyrosine phosphorylated Syk kinase. The third and unexpected feature was to found that, at the contrary of BCR or of CD19 (herein also analyzed for the first time), CD21 activation triggers dissociation of Cbl-Vav complex. Thus, these results provide the first molecular basis of a new signal transduction pathway specifically triggered by CD21 activation

Sensorimotor and cognitive deficits after transient middle cerebral artery occlusion in the mouse.

Whereas behavioral impairments after stroke are increasingly studied in the rat, little is known about the long-term functional consequences of focal ischemia in the mouse. To address this issue, Swiss mice underwent transient (60 min) intraluminal occlusion of the middle cerebral artery (MCAo) or sham surgery. Sensorimotor (chimney, accelerating rotarod, pole, corner, adhesive removal and staircase tests) and cognitive (passive avoidance and Morris water maze) performances were regularly assessed during 1 month, after which the final histological lesion was measured. Motor coordination and balance, assessed by the chimney and rotarod tests, were transiently altered by MCAo. Moreover, bradykinesia was evidenced by the pole test. The most striking and long-lasting (1 month) sensorimotor deficits were postural asymmetries on the corner test, bilateral skilled forepaw reaching deficits on the staircase test and a contralateral sensorimotor impairment on the adhesive removal test. MCAo animals showed normal spatial learning abilities on the Morris water maze test, but they displayed learning deficits measured by the passive avoidance test. This latter deficit was significantly correlated with both cortical and striatal damage. Our findings demonstrate the usefulness of three tests that had never been reported in the mouse after ischemia: the adhesive removal, staircase and pole tests, which showed deficits 1 month after ischemia and should therefore constitute meaningful tools in mice for assessing both neuroprotective and regenerative therapies in stroke preclinical studies

The hypoxia-associated factor HAF, a potential therapeutic target for glioblastoma?

CERVOXYNational audienc

An analogue of heparan sulfate as a novel neuroprotective and neuroregenerative agent for ischemic stroke

CERVOXYInternational audienc

HAF inhibition in glioma cells reduces tumor growth without modifying the efficacy of chemo- and adiotherapy.

CERVOXYInternational audienc

HAF: a potential mediator in glioblastoma growth?

CERVOXYNational audienc

An analogue of heparan sulfate as a novel neuroprotective and neuroregenerative agent for ischemic stroke

CERVOXYInternational audienc

Vasculature and white matter follow-up after brain radiotherapy: preclinical study using multiparametric imaging and immunohistochemistry

CERVOXYInternational audienc