Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions.
Nef of primate lentiviruses is critical for high levels of viremia and the progression to AIDS. Nef associates with and activates a serine/threonine kinase (Nef-associated kinase [NAK]) via the small GTPases Rac1 and Cdc42. We identified the protooncogene and guanine nucleotide exchange factor Vav as the specific binding partner of Nef proteins from HIV-1 and SIV. The interaction between Nef and Vav led to increased activity of Vav and its downstream effectors. Both cytoskeletal changes and the activation of c-Jun N-terminal kinase (JNK) were observed. Furthermore, a dominant-negative Vav protein inhibited NAK activation and viral replication. Thus, the interaction between Nef and Vav initiates a signaling cascade that changes structural and physiological parameters in the infected cell.
Howard Hughes Medical Institute, Department of Medicine, University of California at San Francisco 94143-0703, USA.
O T
OT
Fackler
W
W
Luo
M
M
Geyer
A S
AS
Alberts
B M
BM
Peterlin
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D048429:Cell Size; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D015693:Gene Products, nef / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014779:Virus Replication; D020764:cdc42 GTP-Binding Protein; D054311:nef Gene Products, Human Immunodeficiency Virus; D054462:p21-Activated Kinases; D018909:src Homology Domains
D018797:Cell Cycle Proteins; D015693:Gene Products, nef; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011993:Recombinant Fusion Proteins; C496618:VAV1 protein, human; D054311:nef Gene Products, Human Immunodeficiency Virus; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein