Signaling via Shc family adapter proteins

Ravichandran, Kodi S.

doi:10.1038/sj.onc.1204776

Cited by 387 publications

(386 citation statements)

References 98 publications

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“…PDGF-induced phosphorylation of LRP also produces a docking site for Shc, a group of three homologous adapter proteins that contain a carboxy-terminal Src-homology 2 (SH2), and an amino-terminal PTB domain that is involved in signal transduction by protein tyrosine kinases (Loukinova et al, 2002). Specifically, Shc has been reported to couple activated growth factor receptors to signaling pathways that regulate the proliferation of mammalian cells and plays a role in activation of MAPK (Pelicci et al,1992;Ravichandran, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…In analogy with the activation of LRP1 by PDGF-BB, which leads to activation of Src kinases and Shc, with the participation of PDGF receptor ␤ (see above and Loukinova et al, 2002), we suggest that TSPs may function similarly to elicit a coordinated response from the VLDL and VEGFA receptors. Because PDGF functions as an important mitogen for mesenchymal cells (Heldin and Westermark, 1999) and activated Shc clearly plays a role in the activation of MAPK (Ravichandran, 2001), similarities are likely to exist between the downstream signaling pathways that are engaged by the interactions of PDGF-BB, LRP1, and PDGF receptor ␤ on the one hand and TSPs, VLDLR, and VEGFR on the other.…”

Section: Discussionmentioning

confidence: 99%

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Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Oganesian¹,

Armstrong

Migliorini

et al. 2008

MBoC

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TSPs 1 and 2 function as endogenous inhibitors of angiogenesis. Although thrombospondins (TSPs) have been shown to induce apoptosis in HMVECs, we reasoned that a homeostatic mechanism would also be needed to inhibit EC growth without causing cell death, e.g., in the maintenance of a normal vascular endothelium. HMVECs, cultured in low serum, responded to VEGF with an increase in [ 3 H]thymidine incorporation that was inhibited by TSPs and was accompanied by decreases in the phosphorylation of Akt and MAPK, without an increase in apoptosis. RAP, an inhibitor of the low-density lipoprotein (LDL) family of endocytic receptors, and blocking antibodies to VLDLR were as effective as TSPs in the inhibition of thymidine uptake in response to VEGF, and the effects of these agents were not additive. Supportive evidence for the role of the VLDLR in mediating this inhibition was provided by the demonstration of a high-affinity interaction between TSPs and the VLDLR. We propose that TSP1 and TSP2, together with the VLDLR, initiate a nonapoptotic pathway for maintenance of the normal adult vascular endothelium in a quiescent state, similar to that invoked for the regulation of mitogenesis by PDGF, but involving signaling via the VLDLR rather than LRP1. INTRODUCTIONAlthough thrombospondins (TSPs) 1 and 2 perform multiple functions during mammalian development and in response to injury (Murphy-Ullrich and Poczatek, 2000;Bornstein, 2001;Kyriakides and Bornstein, 2003;Adams and Lawler, 2004), these proteins are best known for their ability to inhibit angiogenesis (Adams, 2001;Lawler, 2002;Armstrong and Bornstein, 2003). Of particular interest is the capability of TSPs to inhibit tumor growth and metastatic spread (Lawler and Detmar, 2004) and consequently the potential of these proteins to serve as a basis for the development of therapeutic antiangiogenic agents (Zhang and Lawler, 2007).In view of these properties, it is to be expected that substantial efforts have been made to understand the mechanisms by which the growth of blood vessels can be inhibited by TSPs. The antiangiogenic activity of TSPs was first recognized by Bouck and coworkers, who identified the product of a tumor suppressor gene in hamster cells as a 140-kDa fragment of TSP1 (Rastinejad et al., 1989;Good et al., 1990). Subsequently, an analysis of the phenotype of the TSP2-null mouse and studies of wound healing and the foreign body reaction in these mice confirmed that TSP2 also possessed potent antiangiogenic properties (Kyriakides et al., 1998a;Kyriakides and Bornstein, 2003).The mechanisms by which TSPs inhibit angiogenesis are complex and comprise both indirect and direct effects on endothelial cells (ECs; Zhang and Lawler, 2007). Indirect effects include direct binding and clearance of a number of growth factors, including vascular endothelial growth factor (VEGF)-A (Greenaway et al., 2007), as well as inhibition of mobilization of growth factors from matrix stores, and clearance of TSP/metalloproteinase complexes from the pericellular environment by the ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Oganesian¹,

Armstrong

Migliorini

et al. 2008

MBoC

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“…1 Although the domain organization is identical in the three isoforms, p66Shc not only fails to activate Ras, but competitively inhibits signaling by the other isoforms. [2][3][4] Furthermore, p66Shc is implicated in signaling pathways linking oxidative stress to apoptosis.…”

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confidence: 99%

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

et al. 2006

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p66Shc, a redox enzyme that enhances reactive oxygen species (ROS) production by mitochondria, promotes T cell apoptosis. We have addressed the mechanisms regulating p66Shc-dependent apoptosis in T cells exposed to supraphysiological increases in [Ca 2 þ ] c . p66Shc expression resulted in profound mitochondrial dysfunction in response to the Ca 2 þ ionophore A23187, as revealed by dissipation of mitochondrial transmembrane potential, cytochrome c release and decreased ATP levels. p66Shc expression also caused a dramatic alteration in the cells' Ca 2 þ -handling ability, which resulted in Ca 2 þ overload after A23187 treatment. The impairment in Ca 2 þ homeostasis was ROS dependent and caused by defective Ca 2 þ extrusion due at least in part to decreased plasma membrane ATPase (PMCA) expression. Both effects of p66Shc required Ca 2 þ -dependent serine-36 phosphorylation. The mitochondrial effects of p66Shc were potentiated by but not strictly dependent on the rise in [Ca 2 þ ] c . Thus, Ca 2 þ -dependent p66Shc phosphorylation causes both mitochondrial dysfunction and impaired Ca 2 þ homeostasis, which synergize in promoting T cell apoptosis.

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“…Shc is an adapter protein, its tyrosine is phosphorylated by several di¡erent types of receptors (growth factor receptors, antigen receptors, cytokine receptors, G protein-coupled receptors and hormone receptors, for review see [10]). The real role Shc plays in signal transduction is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…There are two pathways used by EGFR to activate the MAPK cascade, Shc-dependent and Shc-independent [6,7]. Although Shc-mediated MAPK activation has been well established [8,9], dominant negative Shc or loss of Shc expression often results in only a partial loss of MAPK activation [10]. It remains unclear how much Shc contributes to MAPK activation.…”

Section: Introductionmentioning

confidence: 99%

Shc‐dependent pathway is redundant but dominant in MAPK cascade activation by EGF receptors: a modeling inference

Gong¹,

Zhao²

2003

FEBS Letters

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In cell signaling cascades, one stimulus often leads to various physiological functions by multiple pathways. Perturbation of one pathway by blocking or overexpressing one of its components will result in changes in multiple pathways and multiple cell functions. Thus, it is important to reveal the relative contribution of each pathway to each function in order to assess the consequence of perturbations (e.g. drug delivery). By exploring an established mathematical model, the Shc-dependent pathway is found to be both redundant and dominant during activation of the mitogen-activated protein kinase cascade by epidermal growth factor receptor (EGFR). Its dominance results from the majority consumption of the common precursor ((EGF-EGFR*)2-GAP) by this pathway. The key steps for the dominance are the binding and phosphorylation of Shc. In conclusion, cells may prefer the long Shc-dependent pathway to the short Shc-independent pathway. ß

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Signaling via Shc family adapter proteins

Cited by 387 publications

References 98 publications

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

Thrombospondins Use the VLDL Receptor and a Nonapoptotic Pathway to Inhibit Cell Division in Microvascular Endothelial Cells

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

Shc‐dependent pathway is redundant but dominant in MAPK cascade activation by EGF receptors: a modeling inference

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