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Src kinase modulates the activation, transport and signalling dynamics of fibroblast growth factor receptors.

ABSTRACT: The non-receptor tyrosine kinase Src is recruited to activated fibroblast growth factor receptor (FGFR) complexes through the adaptor protein factor receptor substrate 2 (FRS2). Here, we show that Src kinase activity has a crucial role in the regulation of FGFR1 signalling dynamics. Following receptor activation by ligand binding, activated Src is colocalized with activated FGFR1 at the plasma membrane. This localization requires both active Src and FGFR1 kinases, which are inter-dependent. Internalization of activated FGFR1 is associated with release from complexes containing activated Src. Src-mediated transport and subsequent activation of FGFR1 require both RhoB endosomes and an intact actin cytoskeleton. Chemical and genetic inhibition studies showed strikingly different requirements for Src family kinases in FGFR1-mediated signalling; activation of the phosphoinositide-3 kinase-Akt pathway is severely attenuated, whereas activation of the extracellular signal-regulated kinase pathway is delayed in its initial phase and fails to attenuate.

SUBMITTER: Sandilands E

PROVIDER: S-EPMC2267225 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Src kinase modulates the activation, transport and signalling dynamics of fibroblast growth factor receptors.

Sandilands Emma E Akbarzadeh Shiva S Vecchione Anna A McEwan David G DG Frame Margaret C MC Heath John K JK

EMBO reports 20071102 12

The non-receptor tyrosine kinase Src is recruited to activated fibroblast growth factor receptor (FGFR) complexes through the adaptor protein factor receptor substrate 2 (FRS2). Here, we show that Src kinase activity has a crucial role in the regulation of FGFR1 signalling dynamics. Following receptor activation by ligand binding, activated Src is colocalized with activated FGFR1 at the plasma membrane. This localization requires both active Src and FGFR1 kinases, which are inter-dependent. Inte ...[more]

PMID: 17975556

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Project description:Background and purposeAlthough opioids have been reported to affect glucose homeostasis, relatively little is known on the role of ?-opioid receptors. We have investigated the regulation of glucose transport by human ?-opioid receptors expressed in Chinese hamster ovary cells.Experimental approachThe uptake of [(3)H]-2-deoxy-D-glucose and 3-O-[methyl-[(3)H]]-D-glucose in response to ?-opioid receptor ligands and the expression of GLUT1, GLUT3 and GLUT4 glucose transporters were examined. Moreover, the effects of intracellular signal transduction inhibitors on ?-opioid receptor-regulated [(3)H]-2-deoxy-D-glucose uptake and protein phosphorylation were investigated.Key resultsActivation of ?-opioid receptors rapidly stimulated [(3)H]-2-deoxy-D-glucose and 3-O-[methyl-[(3)H]]-D-glucose uptakes, which were blocked by the GLUT inhibitors cytochalasin B and phloretin. The stimulation of [(3)H]-2-deoxy-D-glucose uptake that occurred without a change in plasma membrane GLUT1 - required the coupling to G(i) /G(o) proteins - was independent of cAMP and extracellular signal-regulated protein kinases, and was suppressed by blockade of Src and insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinases. Inhibition of phosphatidylinositol 3-kinase (PI3K) by wortmannin or LY294002 and by PI3K?, but not ?, isoform-selective inhibitors greatly reduced the ?-opioid receptor stimulation of glucose uptake. Moreover, the response was attenuated by overexpressing a dominant-negative kinase-deficient Akt form and by chemical inhibition of Akt. Stimulation of ?-opioid receptors increased protein kinase C?/? (PKC?/?) phosphorylation and a selective PKC?/? inhibitor slightly reduced opioid stimulation of glucose uptake.Conclusions and implications?-Opioid receptors stimulated glucose transport probably by enhancing GLUT1 intrinsic activity through a signalling cascade involving G(i)/G(o), Src, IGF-1R, PI3K?, Akt and, to a minor extent, PKC?/?. This effect may contribute to the opioid regulation of glucose homeostasis in physio-pathological conditions.

Dataset Information

Src kinase modulates the activation, transport and signalling dynamics of fibroblast growth factor receptors.

Publications

Src kinase modulates the activation, transport and signalling dynamics of fibroblast growth factor receptors.

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