T cell receptor engagement leads to the recruitment of IBP, a novel guanine nucleotide exchange factor, to the immunological synapse.
Reorganization of the actin cytoskeleton is crucial to the formation and function of the immunological synapse. Rho GTPases are critical mediators of cytoskeletal reorganization, and their activity at the synapse is likely to be stringently regulated. Guanine nucleotide exchange factors (GEFs) belonging to the Dbl family of proteins represent one major class of proteins that regulate the activity of Rho GTPases. Here we demonstrate that IBP, a homologue of SWAP-70, is a novel GEF for Rac1 and Cdc42 in T lymphocytes, which is recruited to the immunological synapse upon engagement of the antigen receptor. Mutational analysis supports a model whereby IBP is inactive in unstimulated cells. Upon engagement of the T cell receptor, its GEF activity is enhanced by tyrosine phosphorylation, as well as by binding newly generated phosphatidylinositol 3,4,5-trisphosphate. Although it is known that T cell receptor engagement leads to the recruitment of Vav to the immunological synapse, these findings indicate that other GEFs, such as IBP, also relocalize to this intercellular region. The recruitment and activation of distinct classes of GEFs may allow for precise control of Rho GTPase function at the crucial interface between T cells and antigen presenting cells.
Gupta
Sanjay
S
Departments of Medicine and Medicine and Pharmacology, Columbia University, New York, New York 10032, USA.
Fanzo
Jessica C
JC
Hu
Chuanmin
C
Cox
Dianne
D
Jang
So Young
SY
Lee
Andrea E
AE
Greenberg
Steven
S
Pernis
Alessandra B
AB
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D017252:CD3 Complex; C479750:DEF6 protein, human; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D018129:Phosphatidylinositol Phosphates; D011948:Receptors, Antigen, T-Cell; C491873:SWAP70 protein, human; C113365:Swap70 protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate; D014443:Tyrosine; D004247:DNA; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein