To assess whether phosphorylation of ERM proteins regulates lymphocyte migration and membrane tension we generated transgenic mice whose T-lymphocytes express low levels of ezrin phosphomimetic protein (T567E). In these mice T-cell number in lymph nodes was reduced by 27%. Lymphocyte migration rate in vitro and in vivo in lymph nodes decreased by 18-47%. Lymphocyte membrane tension increased by 71%. Investigations of other possible underlying mechanisms revealed impaired chemokine-induced shape change/lamellipod extension and increased integrin-mediated adhesion. Notably, lymphocyte homing to lymph nodes was decreased by 30%. Unlike most described homing defects, there was not impaired rolling or sticking to lymph node vascular endothelium but rather decreased migration across that endothelium. Moreover, decreased numbers of transgenic T-cells in efferent lymph suggested defective egress. These studies confirm the critical role of ERM dephosphorylation in regulating lymphocyte migration and transmigration. Of particular note, they identify phospho-ERM as the first described regulator of lymphocyte membrane tension, whose increase likely contributes to the multiple defects observed in the ezrin T567E transgenic mice. In collaboration with Dr. Hyun Park, we are investigating alterations in immune cell development in these transgenic mice. Evidence is emerging that T-cell receptor is altered by expression of constitutively active (phosphomimetic) ezrin. Also, as described in our """"""""Lymphocyte membrane-proximal basophilic kinases"""""""" we are investigating via an SLK-knockout mouse, the relevance of SLK, the closest LOK paralog in ERM phosphorylation in lymphocytes.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Maravillas-Montero, Jose L; Gillespie, Peter G; Patino-Lopez, Genaro et al. (2011) Myosin 1c participates in B cell cytoskeleton rearrangements, is recruited to the immunologic synapse, and contributes to antigen presentation. J Immunol 187:3053-63
Liu, Yin; Belkina, Natalya V; Shaw, Stephen (2009) HIV infection of T cells: actin-in and actin-out. Sci Signal 2:pe23
Hao, Jian-Jiang; Liu, Yin; Kruhlak, Michael et al. (2009) Phospholipase C-mediated hydrolysis of PIP2 releases ERM proteins from lymphocyte membrane. J Cell Biol 184:451-62
Belkina, Natalya V; Liu, Yin; Hao, Jian-Jiang et al. (2009) LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation. Proc Natl Acad Sci U S A 106:4707-12