Distinct effectors of platelet-derived growth factor receptor-α 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 PDGFR␣ or PDGFR␤ is embryonic lethal. In Xenopus embryos, disruption of PDGFR␣ signaling causes migrating anterior mesoderm cells to lose direction and undergo apoptosis through the mitochondrial pathway. To understand the mechanism of PDGFR␣ function in this process, we have analyzed all known effectorbinding sites in vivo. By using a chemical inducer of dimerization to activate chimera PDGFR␣s, we have identified a role for phospholipase C␥ (PLC␥) in protecting cells from death. PDGFR␣-mediated cell survival requires PLC␥ and phosphatidylinositol 3-kinase signaling, and that PDGFR␣ with binding sites for these two signaling factors is sufficient for this activity. Other effectors of PDGFR␣ signaling, Shf, SHP-2, and Crk, are not required for this process. Thus, our findings show that PDGFR␣ signaling through PLC␥ 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.apoptosis ͉ gastrulation ͉ phospholipase C␥ ͉ Xenopus

SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans

“…Previous studies by uncoupling individual signaling pathways from PDGFRα using a series of F-to-Y mutants revealed unequal contributions of each signaling pathway emanating from PDGFRα activation (11,12,14). Our in vivo and biochemical data corroborate these reports.…”

“…In particular, PI3K has been identified as the major effector of PDGFRα signaling in vitro and in vivo (10,12,13). SFKs and PLCγ contribute to some but not all PDGFRα functions (10,(12)(13)(14), whereas SHP-2 is not required for cell survival during Xenopus embryogenesis (12). However, contributions of each of these signaling modules to glioma formation have not to our knowledge been demonstrated.…”

“…Previous studies using genetic and biochemical approaches have defined the roles of signaling molecules in PDGFRα-mediated cellular functions by specific tyrosine-to-phenylalanine (Y-to-F) mutations ( Figure 5A) (10,12,13). To investigate the impact of these PDGFRα mutations on tumorigenesis, we separately expressed WT PDGFRα or various PDGFRα mutants in Ink4a/ Arf -/-mAsts.…”

“…Mice deficient in PDGFRα or PDGF-A or engineered to separately express PDGFRα with mutations of the individual p-Y sites show alterations in cellular behavior and embryo development (9,11). In particular, PI3K has been identified as the major effector of PDGFRα signaling in vitro and in vivo (10,12,13). SFKs and PLCγ contribute to some but not all PDGFRα functions (10,(12)(13)(14), whereas SHP-2 is not required for cell survival during Xenopus embryogenesis (12).…”

PDGF-A controls mesoderm cell orientation and radial intercalation duringXenopusgastrulation

“…In addition, PDGF-A has functions other than cell orientation in the embryo. It prevents apoptosis in the mesoderm of Xenopus (Van Stry et al, 2004;Van Stry et al, 2005), and regulates N-cadherin expression in the chick (Yang et al, 2008). In zebrafish, PDGF-A is part of a signaling pathway involving PI3K and PKB, which stimulates the formation of PCM cell protrusions during gastrulation (Montero et al, 2003).…”