Activation of focal adhesion kinase by hepatitis B virus HBx protein: multiple functions in viral replication.
The hepatitis B virus (HBV) X protein (HBx) is a multifunctional regulator of cellular signal transduction and transcription pathways and has a critical role in HBV replication. Much of the cytoplasmic signal transduction activity associated with HBx expression and its stimulation of viral replication is attributable to HBx-induced activation of calcium signaling pathways involving Pyk2 and Src tyrosine kinases. To further characterize upstream signal transduction pathways that are required for HBx activity, including activation of Src and mitogen-activated protein kinase (MAPK) cascades, we determined whether focal adhesion kinase (FAK), a known regulator of Src family kinases and the other member of the Pyk2/FAK kinase family, is activated by HBx. We report that HBx activates FAK and that FAK activation is important for multiple HBx functions. Dominant inhibiting forms of FAK blocked HBx activation of Src kinases and downstream signal transduction, HBx stimulation of NF-kappaB and AP-1-dependent transcription, and HBV DNA replication. We also demonstrate that HBx-induced activation of FAK is dependent on cellular calcium signaling, which is modulated by HBx. Moreover, prolonged expression of HBx increases both FAK activity and its level of expression. FAK activation may play a role in cellular transformation and cancer progression. HBx stimulation of FAK activity and abundance may also be relevant as a potential cofactor in HBV-associated hepatocellular carcinoma.
Bouchard
Michael J
MJ
Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
Wang
Lihua
L
Schneider
Robert J
RJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004261:DNA Replication; D004279:DNA, Viral / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication
D004279:DNA, Viral; D016328:NF-kappa B; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D019000:Phosphotyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D002118:Calcium