title: HIV-1 Tat binds to SH3 domains: cellular and viral outcome of Tat/Grb2 interaction.
abstract: The Src-homology 3 (SH3) domain is one of the most frequent protein recognition modules (PRMs), being represented in signal transduction pathways and in several pathologies such as cancer and AIDS. Grb2 (growth factor receptor-bound protein 2) is an adaptor protein that contains two SH3 domains and is involved in receptor tyrosine kinase (RTK) signal transduction pathways. The HIV-1 transactivator factor Tat is required for viral replication and it has been shown to bind directly or indirectly to several host proteins, deregulating their functions. In this study, we show interaction between the cellular factor Grb2 and the HIV-1 trans-activating protein Tat. The binding is mediated by the proline-rich sequence of Tat and the SH3 domain of Grb2. As the adaptor protein Grb2 participates in a wide variety of signaling pathways, we characterized at least one of the possible downstream effects of the Tat/Grb2 interaction on the well-known IGF-1R/Raf/MAPK cascade. We show that the binding of Tat to Grb2 impairs activation of the Raf/MAPK pathway, while potentiating the PKA/Raf inhibitory pathway. The Tat/Grb2 interaction affects also viral function by inhibiting the Tat-mediated transactivation of HIV-1 LTR and viral replication in infected primary microglia.
authors: Temple University School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA, USA.
authors: Slava
authors: S
authors: Rom
authors: Marco
authors: M
authors: Pacifici
authors: Giovanni
authors: G
authors: Passiatore
authors: Susanna
authors: S
authors: Aprea
authors: Agnieszka
authors: A
authors: Waligorska
authors: Luis
authors: L
authors: Del Valle
authors: Francesca
authors: F
authors: Peruzzi
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D017628:Microglia / Q000378:metabolism / Q000473:pathology / Q000502:physiology* / Q000821:virology; D008969:Molecular Sequence Data; D011485:Protein Binding; D015398:Signal Transduction; D014779:Virus Replication / Q000502:physiology; D018909:src Homology Domains; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism* / Q000502:physiology
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; D048049:Extracellular Signal-Regulated MAP Kinases