Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14
Grb14 belongs to the Grb7 family of adapters and was recently identified as a partner of the insulin receptor (IR). Here we show that Grb14 inhibits in vitro IR substrate phosphorylation. Grb14 does not alter the K(m) for ATP and behaves as an uncompetitive inhibitor for the IR substrate. Similar experiments performed with other members of the Grb7 family, Grb7 and Grb10, and with IGF-1 receptor argue in favor of a specific inhibition of the IR catalytic activity by Grb14. The IR-interacting domain of Grb14, the PIR, is sufficient for the inhibitory effect of Grb14, whereas the SH2 domain has no effect on IR catalytic activity. In Chinese hamster ovary (CHO) cells overexpressing both IR and Grb14, Grb14 binds to the IR as early as 1 min after insulin stimulation, and the two proteins remain associated. When interacting with Grb14, the IR is protected against tyrosine phosphatases action and therefore maintained under a phosphorylated state. However, the binding of Grb14 to the IR induces an early delay in the activation of Akt and ERK1/2 in CHO-IR cells, and ERK1/2 are less efficiently phosphorylated. These findings show that Grb14 is a direct inhibitor of the IR catalytic activity and could be considered as a modulator of insulin signaling.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2002 |
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| Erschienen: |
2002 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:277 |
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| Enthalten in: |
The Journal of biological chemistry - 277(2002), 7 vom: 15. Feb., Seite 4845-52 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Béréziat, Veronique [VerfasserIn] |
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| Anmerkungen: |
Date Completed 21.03.2002 Date Revised 03.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM116182008 |
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| 100 | 1 | |a Béréziat, Veronique |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14 |
| 264 | 1 | |c 2002 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
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| 500 | |a Date Revised 03.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Grb14 belongs to the Grb7 family of adapters and was recently identified as a partner of the insulin receptor (IR). Here we show that Grb14 inhibits in vitro IR substrate phosphorylation. Grb14 does not alter the K(m) for ATP and behaves as an uncompetitive inhibitor for the IR substrate. Similar experiments performed with other members of the Grb7 family, Grb7 and Grb10, and with IGF-1 receptor argue in favor of a specific inhibition of the IR catalytic activity by Grb14. The IR-interacting domain of Grb14, the PIR, is sufficient for the inhibitory effect of Grb14, whereas the SH2 domain has no effect on IR catalytic activity. In Chinese hamster ovary (CHO) cells overexpressing both IR and Grb14, Grb14 binds to the IR as early as 1 min after insulin stimulation, and the two proteins remain associated. When interacting with Grb14, the IR is protected against tyrosine phosphatases action and therefore maintained under a phosphorylated state. However, the binding of Grb14 to the IR induces an early delay in the activation of Akt and ERK1/2 in CHO-IR cells, and ERK1/2 are less efficiently phosphorylated. These findings show that Grb14 is a direct inhibitor of the IR catalytic activity and could be considered as a modulator of insulin signaling | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Insulin |2 NLM | |
| 650 | 7 | |a Proteins |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 650 | 7 | |a Recombinant Fusion Proteins |2 NLM | |
| 650 | 7 | |a GRB7 Adaptor Protein |2 NLM | |
| 650 | 7 | |a 149058-53-7 |2 NLM | |
| 650 | 7 | |a GRB10 Adaptor Protein |2 NLM | |
| 650 | 7 | |a 151441-47-3 |2 NLM | |
| 650 | 7 | |a Glutathione Transferase |2 NLM | |
| 650 | 7 | |a EC 2.5.1.18 |2 NLM | |
| 650 | 7 | |a Protein-Tyrosine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Receptor, Insulin |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinase 3 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Mitogen-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 700 | 1 | |a Kasus-Jacobi, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Perdereau, Dominique |e verfasserin |4 aut | |
| 700 | 1 | |a Cariou, Bertrand |e verfasserin |4 aut | |
| 700 | 1 | |a Girard, Jean |e verfasserin |4 aut | |
| 700 | 1 | |a Burnol, Anne-Françoise |e verfasserin |4 aut | |
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