The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein-Barr virus LMP2A membrane protein.
The Epstein-Barr virus latency-associated membrane protein LMP2A has been shown to activate the survival kinase Akt in epithelial and B cells in a phosphoinositide 3-kinase-dependent fashion. In this study, we demonstrate that the signalling scaffold Shb associates through SH2 and PTB domain interactions with phosphorylated tyrosine motifs in the LMP2A N-terminal tail. Additionally, we show that mutation of tyrosines in these motifs as well as shRNA-mediated downregulation of Shb leads to a loss of constitutive Akt-activation in LMP2A-expressing cells. Furthermore, utilization by Shb of the LMP2A ITAM motif regulates stability of the Syk tyrosine kinase in LMP2A-expressing cells. Our data set the precedent for viral utilization of the Shb signalling scaffold and implicate Shb as a regulator of LMP2A-dependent Akt activation.
Matskova
L V
LV
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden. ludmat@ki.se
Helmstetter
C
C
Ingham
R J
RJ
Gish
G
G
Lindholm
C K
CK
Ernberg
I
I
Pawson
T
T
Winberg
G
G
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D001402:B-Lymphocytes / Q000821:virology*; D001665:Binding Sites; D002460:Cell Line; D002461:Cell Line, Transformed; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C490081:SHB protein, human; D014763:Viral Matrix Proteins; D014443:Tyrosine; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051057:Proto-Oncogene Proteins c-akt