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Receptor-tyrosine-kinase- and Gβγ-mediated MAP kinase activation by a common signalling pathway

Abstract

MITOGEN-ACTIVATED protein (MAP) kinases mediate the phos-phorylation and activation of nuclear transcription factors that regulate cell growth1. MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrinsic tyrosine kinase activity, or G-protein-coupIed receptors (GPCR)2–4. RTK-mediated mitogenic signalling involves a series of SH2- and SH3-dependent protein-protein interactions between tyrosine-phosphorylated receptor, She, Grb2 and Sos, resulting in Ras-dependent MAP kinase activation5–7. The βγ sub-units of heterotrimeric G proteins (Gβγ) also mediate Ras-dependent MAP kinase activation8–10 by an as-yet unknown mechanism. Here we demonstrate that activation of MAP kinase by Gi-coupled receptors is preceded by the Gβγ-mediated tyrosine phosphorylation of She, leading to an increased functional association between She, Grb2 and Sos. Moreover, disruption of the Shc–Grb2–Sos complex blocks Gβγ-mediated MAP kinase activation, indicating that Gβγ does not mediate MAP kinase activation by a direct interaction with Sos. These results indicate that Gβγ-mediated MAP kinase activation is initiated by a tyrosine phosphorylation event and proceeds by a pathway common to both GPCRs and RTKs.

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Blesen, T., Hawes, B., Luttrell, D. et al. Receptor-tyrosine-kinase- and Gβγ-mediated MAP kinase activation by a common signalling pathway. Nature 376, 781–784 (1995). https://doi.org/10.1038/376781a0

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