title: The GTPase regulatory proteins Pix and Git control tissue growth via the Hippo pathway.
abstract: The Salvador-Warts-Hippo (Hippo) pathway is a conserved regulator of organ size and is deregulated in human cancers. In epithelial tissues, the Hippo pathway is regulated by fundamental cell biological properties, such as polarity and adhesion, and coordinates these with tissue growth. Despite its importance in disease, development, and regeneration, the complete set of proteins that regulate Hippo signaling remain undefined. To address this, we used proteomics to identify proteins that bind to the Hippo (Hpo) kinase. Prominent among these were PAK-interacting exchange factor (known as Pix or RtGEF) and G-protein-coupled receptor kinase-interacting protein (Git). Pix is a conserved Rho-type guanine nucleotide exchange factor (Rho-GEF) homologous to Beta-PIX and Alpha-PIX in mammals. Git is the single Drosophila melanogaster homolog of the mammalian GIT1 and GIT2 proteins, which were originally identified in the search for molecules that interact with G-protein-coupled receptor kinases. Pix and Git form an oligomeric scaffold to facilitate sterile 20-like kinase activation and have also been linked to GTPase regulation. We show that Pix and Git regulate Hippo-pathway-dependent tissue growth in D. melanogaster and that they do this in parallel to the known upstream regulator Fat cadherin. Pix and Git influence activity of the Hpo kinase by acting as a scaffold complex, rather than enzymes, and promote Hpo dimerization and autophosphorylation of Hpo's activation loop. Therefore, we provide important new insights into an ancient signaling network that controls the growth of metazoan tissues.
authors.affiliation: Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Lucas G
authors.initials: LG
authors.lastname: Dent
authors.affiliation: Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Carole L C
authors.initials: CL
authors.lastname: Poon
authors.affiliation: Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Joffrey L
authors.initials: JL
authors.lastname: Degoutin
authors.affiliation: Department of Biology, Providence College, Providence, RI 02918, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Tipping
authors.affiliation: Department of Biology, University of Massachusetts Boston, Boston, MA 02125, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Veraksa
authors.affiliation: Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, 7 St Andrews Place, East Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Pathology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: kieran.harvey@petermac.org.
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Harvey
mesh_terms: D000818:Animals; D019281:Dimerization; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D020555:GTP-Binding Protein Regulators / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D006128:Growth / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D020555:GTP-Binding Protein Regulators; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D064067:Rho Guanine Nucleotide Exchange Factors; C534509:Git protein, Drosophila; C577401:rtGEF protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases