Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment

Yang, Jinlin; Symes, Karen; Mercola, Mark; Schreiber, Stuart L.

doi:10.1016/s0960-9822(98)70015-6

Cited by 40 publications

(35 citation statements)

References 37 publications

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“…Thus, the intracellular portion of a wt or a substituted PDGFR␣ is fused to three FKBP12 dimerization domains, which, in turn, are fused to the myristoylation signal from v-Src for targeting to the plasma membrane (Fig. 1C) (14). These iPDGFR␣s are activated by addition of the synthetic ligand, AP1510 (15).…”

Section: Results Ipdgfr␣ Activation Restores Mesoderm Cell Survival Tmentioning

confidence: 99%

Distinct effectors of platelet-derived growth factor receptor-α signaling are required for cell survival during embryogenesis

Stry

Kazlauskas

Schreiber

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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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

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Section: Results Ipdgfr␣ Activation Restores Mesoderm Cell Survival Tmentioning

confidence: 99%

Distinct effectors of platelet-derived growth factor receptor-α signaling are required for cell survival during embryogenesis

Stry

Kazlauskas

Schreiber

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…In this case, the chimera contains the extracellular domain of another wild-type receptor, CSF-1R, which may keep the unliganded chimera in a switched-off state. In the case of Yang et al there is background activation of downstream signaling molecules, but the activation levels with a ligand were much higher than those without a ligand (Yang et al 1998). In this case, the chimeric receptor lacks the transmembrane domain which significantly contributes to interchain interaction of receptor chains (Dawson et al 2002).…”

Section: Discussionmentioning

confidence: 96%

“…Therefore, mimicry of insulin signaling would be a promising strategy to realize artificial control of such cellular fates. To this end, several chimeric receptors using the IR signaling domain have been generated (Chaika et al 1997;Yang et al 1998). The fusion proteins composed of FK-binding protein 12 (FKBP12) or the extracellular domain of colony-stimulating factor (CSF)-1 receptor and the intracellular domain of IR transduced a differentiation signal in response to their corresponding ligand, FK1012 or CSF-1, respectively.…”

Section: Introductionmentioning

confidence: 99%

Construction of antibody/insulin receptor chimera for growth induction of mammalian cells

et al. 2013

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The insulin receptor (IR) is expressed ubiquitously in various tissues, where insulin exerts various biological effects on the target cells, such as cellular metabolic changes, cell proliferation and differentiation. Therefore, mimicry of insulin signaling would be a promising strategy to realize artificial control of such cellular fates. In this study, we constructed an antibody/insulin receptor chimera that enables to utilize any antigen as the ligand in principle. We constructed chimeric receptors consisting of antifluorescein single chain Fv (scFv), the extracellular D2 domain of erythropoietin receptor and the transmembrane/intracellular domains of IR (scFv-IR; S-IR). The function of S-IR was evaluated in terms of growth signal transduction in murine pro-B Ba/F3 cells and murine fibroblast NIH/3T3 cells. S-IR exerted IL-3-independent cell growth in Ba/F3 cells, while NIH/ 3T3 cells expressing S-IR acquired growth advantage over parental NIH/3T3 cells in a low-serum condition. S-IR induced phosphorylation of S-IR itself and key signaling molecules downstream of IR. Although antigen-independent activation was significantly observed, S-IR enabled specific amplification of the gene-transduced cells.

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“…Variations on these systems have been used very successfully to induce homodimerization or heterodimerization of receptors (Fig. 3c,d, respectively), including insulin, platelet-derived growth factor (PDGF) and fibroblast growth factor receptors (FGFRs) in vivo (Pownall et al, 2003;Yang et al, 1998).…”

Section: Controlling Protein Function With Small Moleculesmentioning

confidence: 99%

Xenopus: An ideal system for chemical genetics

Wheeler

Liu

2012

Genesis

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Summary: Chemical genetics, or chemical biology, has become an increasingly powerful method for studying biological processes. The main objective of chemical genetics is the identification and use of small molecules that act directly on proteins, allowing rapid and reversible control of activity. These compounds are extremely powerful tools for researchers, particularly in biological systems that are not amenable to genetic methods. In addition, identification of small molecule interactions is an important step in the drug discovery process. Increasingly, the African frog Xenopus is being used for chemical genetic approaches. Here, we highlight the advantages of Xenopus as a first-line in vivo model for chemical screening as well as for testing reverse engineering approaches. genesis 50: 207-218, 2012. V V C 2012 Wiley Periodicals, Inc.

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Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment

Cited by 40 publications

References 37 publications

Distinct effectors of platelet-derived growth factor receptor-α signaling are required for cell survival during embryogenesis

Distinct effectors of platelet-derived growth factor receptor-α signaling are required for cell survival during embryogenesis

Construction of antibody/insulin receptor chimera for growth induction of mammalian cells

Xenopus: An ideal system for chemical genetics

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