The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway

Dance, Marie; Montagner, Alexandra; Salles, Jean‐Pierre; Yart, Armelle; Raynal, Patrick

doi:10.1016/j.cellsig.2007.10.002

Cited by 294 publications

(296 citation statements)

References 49 publications

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“…48,49 Further, SHP-2 dephosphorylation of paxillin, with the subsequent activation of src kinase, is one mechanism for the activation of ERK. 50,51 Our data therefore suggest that the stimulation of filopodia formation mediated by PECAM-1 involves SHP-2-mediated activation of ERK.…”

Section: Acknowledgementsmentioning

confidence: 75%

“…[51][52][53][54] It is important to note, however, that PECAM-1 is expressed at persistently high levels on ECs 17 and thus acute increases in PECAM-1 levels are unlikely to directly mediate an increase in Cdc42 expression during angiogenesis. This therefore suggests that if PECAM-1 regulates Cdc42 expression during angiogenesis, this activity involves changes in the activational state PECAM-1 and/or its interaction with other molecules involved in the regulation of Cdc42.…”

Section: Acknowledgementsmentioning

confidence: 99%

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Modulators of endothelial cell filopodia

DeLisser

2011

Cell Adhesion & Migration

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Section: Acknowledgementsmentioning

confidence: 75%

Section: Acknowledgementsmentioning

confidence: 99%

Modulators of endothelial cell filopodia

DeLisser

2011

Cell Adhesion & Migration

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“…This review will concentrate on publications in the last two years on the SIRPα recognition and constraints on the functional outcome. Detailed analysis of signalling mechanisms is outside the scope of the review although there are recent data [2][3][4][5][6][7][8]; however molecular interactions that influence whether signalling will occur will be discussed.…”

Section: Introductionmentioning

confidence: 99%

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

Barclay

2009

Current Opinion in Immunology

101

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SummarySIRPα is an inhibitory receptor present on myeloid cells that interacts with a widely distributed membrane protein CD47. The activating member SIRPβ, despite extensive sequence similarity to SIRPα in the extracellular region, shows negligible binding to CD47. The SIRPα / CD47 interaction is unusual in that it can lead to bidirectional signalling through both SIRPα and CD47. This review concentrates on the interactions of SIRPα with CD47 where recent data have shed light on the structure of the proteins including determining why the activating SIRPβ does not bind CD47, evidence of extensive polymorphisms and implication for the evolution and function of this protein and paired receptors in general. The interaction may be modified by endocytosis of the receptors, cleavage by proteolysis and through interactions of surfactant proteins.

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“…[1][2][3] Shp2 is thought to be inactive by forming intramolecular folding under unstimulated conditions, whereas it becomes active when the amino-terminal SH2 domains bind to phosphorylated molecules, including Grb2-associated binder (Gab), insulin receptor substrate and fibroblast growth factor receptor substrate, by forming an open conformation. 2,3 It remains unclear how Shp2 is involved in the activation of Erk signal and whether its phosphatase activity of Shp2 is essential for the activation of Ras-Erk signal. Phosphatase-active mutation of Shp2 (a genetic mutation of PTPN11 encoding Asn308Asp, hereafter referred to as N308D) is found in patients with Noonan syndrome, whereas phosphatase-defective mutation (Thr468Met, hereafter referred to as T468M) is found in those with Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth and sensorineural Deafness (LEOPARD) syndrome.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] Shp2 contains two tandem Src homology 2 (SH2) domains, a protein tyrosine phosphatase domain and tyrosine phosphorylation sites. [1][2][3] Shp2 is thought to be inactive by forming intramolecular folding under unstimulated conditions, whereas it becomes active when the amino-terminal SH2 domains bind to phosphorylated molecules, including Grb2-associated binder (Gab), insulin receptor substrate and fibroblast growth factor receptor substrate, by forming an open conformation. 2,3 It remains unclear how Shp2 is involved in the activation of Erk signal and whether its phosphatase activity of Shp2 is essential for the activation of Ras-Erk signal.…”

Section: Introductionmentioning

confidence: 99%

Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase

et al. 2013

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1Shp2 is a positive regulator for Erk activation downstream of receptor tyrosine kinases for growth factors. It has been controversial how Shp2 induces Erk activation. We here demonstrate that EphA2 is responsible for Shp2-mediated Erk activation by phosphorylating Tyr542 and Tyr580 of Shp2 in the cells stimulated with growth factors. In NMuMG mammary epithelial cells stimulated with hepatocyte growth factor (HGF), HGF-dependent Erk phosphorylation was prolonged only in the presence of EphA2. This Erk activation paralleled the phosphorylation of Tyr542/580 of Shp2 and the association of Grb2 with Shp2, suggesting the positive signal involving Grb2 signal to activate Ras-Erk pathway. Immunohistochemical studies of mammary cancer specimens revealed that the cancer progression was associated with both Tyr580 phosphorylation of Shp2 and increased expression of EphA2, which were also correlated with increased Erk phosphorylation. Overexpression of either Shp2Thr468Met (a phosphatase-defective mutant found in Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth and sensorineural Deafness (LEOPARD) syndrome) or Shp2Asn308Asp (a phosphatase-active mutant found in Noonan syndrome) with EphA2 exhibited comparable activation of Erk and stronger activation than wild-type Shp2, suggesting the phosphatase-independent Erk activation. Expression of Shp2Thr468Met with Tyr542/580Phe mutations resulted in the suppression of Erk activation. Phosphatase-active and -inactive, and wild-type Shp2s bound equally to Grb2, suggesting that phosphorylation of Tyr542/580 of Shp2 was essential but not sufficient for Shp2-mediated Erk activation. We found that Gab1 (Grb2-associated binder 1) was involved in the mutant Shp2-mediated Erk activation. Zebrafish injected with Shp2Thr468Met mRNA showed cardiac edema, whereas those depleted of EphA2b showed less phenotype, suggesting that EphA2 might partly account for the phenotype of LEOPARD syndrome. Collectively, tyrosine phosphorylation of Shp2 by EphA2 contributes to the phosphatase-independent Shp2-mediated activation of Erk and might be involved in Shp2-associated diseases.

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The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway

Cited by 294 publications

References 49 publications

Modulators of endothelial cell filopodia

Modulators of endothelial cell filopodia

Signal regulatory protein alpha (SIRPα)/CD47 interaction and function

Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase

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