Abl collaborates with Src family kinases to stimulate actin-based motility of vaccinia virus.
Local activation of Src at the plasma membrane by extracellular vaccinia virus results in a signalling cascade that acts to stimulate actin polymerization beneath the virus to enhance its cell-to-cell spread. Initiation of this signalling cascade involves Src-mediated phosphorylation of tyrosine 112 and 132 of the viral membrane protein A36R. Here we show that recruitment of Src is dependent on its myristoylation and an interaction with A36R upstream of tyrosine 112 and 132. We further show that Src, Fyn and Yes have unique specificities towards these tyrosine residues. Using cell lines deficient in Src, Fyn and Yes, we demonstrate that multiple Src family members can stimulate vaccinia-induced actin polymerization and also uncover a role for Abl family kinases. Additionally, Abl and Arg are able to phosphorylate A36R in vitro and are recruited to vaccinia-induced actin tails. The ability of multiple families of tyrosine kinases to directly phosphorylate A36R ensures robust cell-to-cell spread of vaccinia virus will occur under a variety of cellular conditions.
Newsome
Timothy P
TP
Cell Motility Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, WC2A 3PX, London, UK.
Weisswange
Ina
I
Frischknecht
Friedrich
F
Way
Michael
M
D000199:Actins / Q000502:physiology*; D000818:Animals; D001549:Benzamides; D001693:Biological Transport, Active; D002460:Cell Line; D006801:Humans; D000068877:Imatinib Mesylate; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D051076:Proto-Oncogene Proteins c-fyn / Q000037:antagonists & inhibitors / Q000378:metabolism; D051575:Proto-Oncogene Proteins c-yes / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D014616:Vaccinia virus / Q000502:physiology*; D015678:Viral Structural Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000502:physiology*
C400287:A36R protein, Vaccinia virus; C412373:AG 1879; D000199:Actins; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D015678:Viral Structural Proteins; D014443:Tyrosine; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D019061:src-Family Kinases