title: XB130/Tks5 scaffold protein interaction regulates Src-mediated cell proliferation and survival.
abstract: The scaffold protein XB130 regulates cell growth, survival, and migration. Yeast two-hybrid screening suggests that XB130 interacts with another scaffold protein, Tks5. We hypothesized that XB130 and Tks5 form a macromolecular complex to mediate signal transduction cascades for the regulation of cell growth and survival. Coimmunoprecipitation demonstrated that XB130 and Tks5 interact endogenously and form a complex with Src tyrosine kinase. Structure-function studies showed that the fifth SH3 domain of Tks5 binds to the N-terminus of XB130, which contains polyproline-rich motifs. Cell growth and survival studies revealed that down-regulation of XB130 and/or Tks5 reduced cell proliferation, resulting in cell cycle inhibition at the G1 phase and increased caspase 3 activity and apoptosis. Moreover, cell proliferation and survival were increased by overexpression of XB130 or Tks5 but decreased when XB130/Tks5 binding was disrupted by overexpression of XB130 N-terminal deleted mutant and/or Tks5 fifth SH3 domain W1108A mutant. Furthermore, down-regulation of XB130 and/or Tks5 inhibited serum- and growth factor-induced Src activation and downstream phosphorylation of PI3K and Akt. Our results suggest that Tks5, similar to XB130, plays a role in cell proliferation and cell survival and that the interaction between XB130 and Tks5 appears to be critical for regulation of Src-mediated cellular homeostasis.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Serisha
authors.initials: S
authors.lastname: Moodley
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hui Bai
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Burton
authors.initials: B
authors.lastname: Yang
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada Department of Surgery, University of Toronto, Toronto, ON M5S 1A8, Canada mingyao.liu@utoronto.ca.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C521126:AFAP1L2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C478582:SH3PXD2A protein, human; D019061:src-Family Kinases