title: Distinct effectors of platelet-derived growth factor receptor-alpha signaling are required for cell survival during embryogenesis.
abstract: Platelet-derived growth factor receptor (PDGFR) signaling is essential for normal embryonic development in many organisms, including frog, mouse, zebrafish, and sea urchin. The mode of action of PDGFR signaling during early development is poorly understood, however, mostly because inhibition of signaling through either the PDGFRalpha or PDGFRbeta is embryonic lethal. In Xenopus embryos, disruption of PDGFRalpha signaling causes migrating anterior mesoderm cells to lose direction and undergo apoptosis through the mitochondrial pathway. To understand the mechanism of PDGFRalpha function in this process, we have analyzed all known effector-binding sites in vivo. By using a chemical inducer of dimerization to activate chimera PDGFRalphas, we have identified a role for phospholipase Cgamma (PLCgamma) in protecting cells from death. PDGFRalpha-mediated cell survival requires PLCgamma and phosphatidylinositol 3-kinase signaling, and that PDGFRalpha with binding sites for these two signaling factors is sufficient for this activity. Other effectors of PDGFRalpha signaling, Shf, SHP-2, and Crk, are not required for this process. Thus, our findings show that PDGFRalpha signaling through PLCgamma and phosphatidylinositol 3-kinase has a protective role in preventing apoptosis in early development. Furthermore, we demonstrate that small molecule inducers of dimerization provide a powerful system to manipulate receptor function in developing embryos.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Van Stry
authors.forename: Andrius
authors.initials: A
authors.lastname: Kazlauskas
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Karen
authors.initials: K
authors.lastname: Symes
mesh_terms: D000818:Animals; D002470:Cell Survival; D004625:Embryo, Nonmammalian / Q000166:cytology* / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D047108:Embryonic Development; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D014981:Xenopus / Q000196:embryology* / Q000378:metabolism*; D029867:Xenopus Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D029867:Xenopus Proteins; C493873:crk2 protein, Xenopus; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; D010738:Type C Phospholipases; D051966:Phospholipase C gamma