The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp.

Kazlauskas, Andrius; Feng, Gen‐Sheng; Pawson, Tony; Valius, Mindaugas

doi:10.1073/pnas.90.15.6939

Cited by 202 publications

(143 citation statements)

References 44 publications

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“…Platelet-derived growth factor receptor is classified as the receptor protein tyrosine kinases that are so named since they are activated when specific tyrosine residues on the intracellular domain of the receptor are phosphorylated. After dimerisation, phosphorylated tyrosine residues interact with Src homology 2 domains of intracellular signalling molecules including PI3K/Akt (Heidaran et al, 1993;Kazlauskas et al, 1993;DeMali et al, 1997;Rosenkranz and Kazlauskas, 1999). In the present study, anti-PDGF antibody reduced phosphorylation of Akt, indicating that PDGF signalling leading to PI3K/Akt activation is suppressed.…”

Section: Discussionsupporting

confidence: 49%

Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

et al. 2004

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Malignant gliomas highly coexpress platelet-derived growth factor (PDGF) and its receptor, suggesting the presence of an autocrine loop. Therefore, disruption of PDGF ligand/receptor complex represents a promising strategy for the treatment of malignant gliomas. However, the mechanisms of the antitumour effect exerted by the inhibition of PDGF-mediated cell growth remain unclear. In the present study, using anti-PDGF neutralising antibody, we investigated the effect of the inhibition of PDGF signalling on malignant glioma U87-MG, D54, and T98G cells with high levels of PDGF-A and -B. As a control, normal fibroblast MRC5 cells expressing low levels of PDGF-A and -B were used. Treatment with anti-PDGF neutralising antibody did not affect the expressions of PDGF-A, PDGF-B, and Akt, but suppressed the level of phosphorylated Akt in tumour cells, indicating the inhibition of PDGF signalling. The cell viability of all malignant glioma cells tested in this study was significantly inhibited in a time-dependent manner following the treatment compared to that of fibroblast cells (Po0.02 to o0.05). The antitumour effect of anti-PDGF antibody was suppressed by the activation of Akt and enhanced by the downregulation of Akt. Interestingly, the inhibition of PDGF signalling induced the development of acidic vesicular organelles and the autophagosome membrane association of the microtubule-associated protein light chain 3, which are characteristic of autophagy, in malignant glioma cells, while apoptotic cell death was not observed. Together these findings imply a new concept of autophagy for PDGF autocrine inhibition in malignant gliomas.

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Section: Discussionsupporting

confidence: 49%

Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

et al. 2004

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“…SHP-2, which has two SH2 domains in its aminoterminal part, has previously been shown to bind with high a nity to Tyr1009 in the PDGF b-receptor (Kazlauskas et al, 1993;Lechleider et al, 1993). Using a peptide library approach, Songyang et al (1993) de®ned Y-I/V-X-V/I/L/P as an optimal sequence for binding to the N-terminal SH2 domain of SHP-2; the identi®ed motif is similar to the sequence surrounding Tyr1009, but not to the sequence surrounding Tyr763.…”

Section: Discussionmentioning

confidence: 99%

“…In order to study the function of Tyr763 phosphorylation in vivo, we mutated Tyr763 to a phenylalanine residue, either singly or together with Tyr1009, a previously identi®ed site for binding of SHP-2 in the PDGF b-receptor (Kazlauskas et al, 1993), and expressed the mutant receptors in PAE cells. Stimulation of cells with PDGF-BB followed by immunoprecipitation with an antiserum against SHP-2 showed coimmunoprecipitation of the PDGF b-receptor in cells expressing the wild-type receptor, while in cells expressing either Y763F or Y1009F mutant receptor, association was dramatically reduced (Figure 3).…”

Section: Identi®cation Of Tyr763 As An Autophosphorylation Site In Thmentioning

confidence: 99%

“…Overexpression of a catalytically compromised SHP-2 protein (Rivard et al, 1995) or microinjection of either a GST-fusion protein containing the SH2 domains of SHP-2 or neutralizing antibodies (Roche et al, 1996) inhibited PDGF-induced mitogenicity. It has previously been shown that Tyr1009 in the PDGF breceptor binds to SHP-2 (Kazlauskas et al, 1993), and that the association between the SH2 domains of SHP-2 and its target proteins triggers activation of the phosphatase activity of SHP-2 Pluskey et al, 1995). Simultaneous occupancy of both SH2 domains by phosphopeptides is required for full activation of the phosphatase activity of SHP-2 (Eck et al, 1996;Jackson et al, 1997;Ohnishi et al, 1996;Pluskey et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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SHP-2 binds to Tyr763 and Tyr1009 in the PDGF β-receptor and mediates PDGF-induced activation of the Ras/MAP kinase pathway and chemotaxis

et al. 1999

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Activation of the b-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2. SHP-2 has also previously been shown to bind to phosphorylated Tyr1009 in the PDGF b-receptor. Porcine aortic endothelial (PAE) cells transfected with a PDGF breceptor in which Tyr763 and Tyr1009 were mutated to phenylalanine residues failed to associate with SHP-2 after ligand stimulation. Morover, PDGF-BB-induced Ras GTP-loading and Erk2 activation were severely compromised in the receptor mutant. Whereas the mitogenic response to PDGF-BB remained at the same level as in cells expressing wild-type PDGF b-receptor, chemotaxis induced by PDGF-BB was signi®cantly decreased in the case of the Y763F/Y1009F mutant cells, suggesting an important role for SHP-2 in chemotactic signaling.

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“…Although the association of SHP-2 with the PDGF receptor (PDGF-R) and the phosphorylation of SHP-2 after PDGF stimulation have been well documented [13][14][15][16], whether the enzyme dephosphorylates the receptor in i o and how it affects the downstream signalling of the receptor are not well defined. In the present study we have transiently co-expressed PDGF-R with several active or inactive forms of SHP-2 in human embryonic kidney 293 cells.…”

Section: Introductionmentioning

confidence: 99%

Tyrosine phosphatase SHP-2 dephosphorylates the platelet-derived growth factor receptor but enhances its downstream signalling

Zhao

1999

Biochemical Journal

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SHP-2 is a widely distributed Src homology 2 (SH2) domain-containing tyrosine phosphatase that is recruited to growth factor receptors on stimulation. We have transiently co-expressed several catalytically active and inactive forms of the enzyme with the platelet-derived growth factor (PDGF) receptor in human embryonic kidney 293 cells. The catalytically active forms of SHP-2 decreased the tyrosine phosphorylation of the receptor, whereas the catalytically inactive forms increased the phosphorylation. However, PDGF-induced activation of the mitogen-activated protein (MAP) kinase pathway was enhanced by the active forms of SHP-2 but decreased by the inactive forms. The results suggest that the PDGF receptor is a physiological substrate of SHP-2 and that SHP-2 has a positive role in the PDGF-stimulated activation of MAP kinase. The dissociation of the receptor phosphorylation from the activation of MAP kinase suggests that signalling through growth factor receptors does not depend merely on their tyrosine phosphorylation.

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The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp.

Cited by 202 publications

References 44 publications

Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

SHP-2 binds to Tyr763 and Tyr1009 in the PDGF β-receptor and mediates PDGF-induced activation of the Ras/MAP kinase pathway and chemotaxis

Tyrosine phosphatase SHP-2 dephosphorylates the platelet-derived growth factor receptor but enhances its downstream signalling

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