A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction

Pelicci, Giuliana; Lanfrancone, Luisa; Grignani, Francesco; McGlade, Jane; Cavallo, Federica; Forni, Guido; Nicoletti, Ildo; Grignani, F; Pawson, Tony; Pelicci, Pier Giuseppe

doi:10.1016/0092-8674(92)90536-l

Cited by 1,287 publications

(1,026 citation statements)

References 49 publications

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“…For instance, when the insulin receptor is stimulated by insulin, it speci®cally recruits the docking molecule IRS-1 through its PTB domain and subsequently phosphorylates IRS-1 on tyrosine residues (Sun et al, 1993). In addition, the epidermal growth factor (EGF) receptor can use the adapter molecules Shc and Gab1 as substrates when stimulated (Pelicci et al, 1992;Holgado-Madruga et al, 1996). To demonstrate that Tek could utilize Dok-R as a substrate, we immunoprecipitated full-length activated Tek from Tektransfected 293T cell lysates and performed in vitro kinase assays using either GST or GST-Dok-R as substrates.…”

Section: In Vivo Association Of Dok-r and Tek In 293t Cellsmentioning

confidence: 99%

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

1998

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Tek/Tie2 is an endothelial cell-speci®c receptor tyrosine kinase that has been shown to play a role in vascular development of the mouse. Targeted mutagenesis of both Tek and its agonistic ligand, Angiopoietin-1, result in embryonic lethality, demonstrating that the signal transduction pathway(s) mediated by this receptor are crucial for normal embryonic development. In an attempt to identify downstream signaling partners of the Tek receptor, we have used the yeast two-hybrid system to identify phosphotyrosine-dependent interactions. Using this approach, we have identi®ed a novel docking molecule called Dok-R, which has sequence and structural homology to p62 dok and IRS-3. Mapping of the phosphotyrosine-interaction domain within Dok-R shows that Dok-R interacts with Tek through a PTB domain. Dok-R is coexpressed with Tek in a number of endothelial cell lines. We show that coexpression of Dok-R with activated Tek results in tyrosine phosphorylation of Dok-R and that rasGAP and Nck coimmunoprecipitate with phosphorylated Dok-R. Furthermore, Dok-R is constitutively bound to Crk presumably through the proline rich tail of Dok-R. The cloning of Dok-R represents the ®rst downstream substrate of the activated Tek receptor, and suggests that Tek can signal through a multitude of pathways.

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Section: In Vivo Association Of Dok-r and Tek In 293t Cellsmentioning

confidence: 99%

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

1998

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“…A polyclonal anti-Shc serum was raised against a GST-Shc SH2 fusion protein (Pelicci et al, 1992). A monoclonal antibody (29B4) and a polyclonal serum (anti-C19) that recognize the human insulin receptor were purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA).…”

Section: Cells Lines and Antibodiesmentioning

confidence: 99%

Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

1999

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Shc and IRS-1 (and their relatives) are cytoplasmic docking proteins that possess phosphotyrosine-binding (PTB) domains, through which they bind speci®c activated receptor tyrosine kinases (RTK). The subsequent phosphorylation of Shc or IRS-1 creates binding sites for the SH2 domains of multiple signaling proteins, leading to the activation of intracellular biochemical pathways. The PTB domains of Shc and IRS-1 both recognize autophosphorylation sites in RTKs with the consensus sequence NPXpY, but show distinct abilities to bind stably to RTKs such as the TrkA nerve growth factor receptor and the insulin receptor. In vitro analysis has suggested that residues N-terminal to the NPXpY motif may determine the a nity with which phosphopeptide ligands are recognized by the Shc and IRS-1 PTB domains. Unlike IRS-1, the Shc PTB domain binds poorly to the insulin-receptor (IR) b subunit in vitro, owing to its low a nity for the NPXpY autophosphorylation site at Tyr 960 of the IR. As a consequence, Shc does not bind stably to the activated IR in cells. We show that substitution of Ser 955, ®ve residues Nterminal to the Tyr 960 autophosphorylation site (the 75 position), with Ile alters the target speci®city of the IR such that it stably associates with Shc in insulinstimulated cells. A triple substitution of the 75, 78 and 79 residues relative to Tyr 960 of the IR to the corresponding amino acids found in the Shc PTB domain binding site of TrkA results in even stronger binding of the IR to Shc in vivo. The variant IRs with enhanced ability to bind Shc showed an increased ability to activate the MAPK pathway in response to insulin stimulation. These results demonstrate that subtle di erences in residues N-terminal to NPXpY autophosphorylation sites determine the ability of RTKs to bind speci®c PTB domain proteins in vivo, and thus modify the signaling properties of activated receptors.

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“…Ligand-stimulation of receptor tyrosine kinases leads to the binding of adaptor proteins, such as Grb2 and Shc (Pelicci et al, 1992), containing Src homology 2 (SH2) or phosphotyrosine-binding (PTB) domains (reviewed in Schlessinger and Ullrich, 1992;Pawson, 1995;. Such adapters, when bound to the phosphorylated receptor, recruit Sos to the plasma membrane, where it activates Ras and, thus, the Raf-MEK1/MEK2-ERKs cascade (reviewed by Marshall, 1995).…”

Section: Introductionmentioning

confidence: 99%

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

et al. 1998

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The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH 2 -terminal protein kinases (JNK). Here we show that triggering the endogenous Ret, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 ®broblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-de®cient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Ret is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42.

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A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction

Cited by 1,287 publications

References 49 publications

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

The Tek/Tie2 receptor signals through a novel Dok-related docking protein, Dok-R

Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

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