Tyrosine Kinases of the Src Family Participate in Signaling to MAP Kinase from both Gqand Gi-Coupled Receptors

Igishi, Tadashi; Gutkind, J. Silvio

doi:10.1006/bbrc.1998.8208

Cited by 71 publications

(68 citation statements)

References 26 publications

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“…In most instances, it appears that G ␤␥ activates MAPK through a pathway that includes considerable overlap with that of typical receptor tyrosine kinase activation (Crespo et al, 1994;Hawes et al, 1995). Specifically, in many cell types, the G ␤␥ subunit activates MAPK in a pathway that is PI3K-, Ras-, and often tyrosine-kinase-dependent as well (Lopez-Ilasaca et al, 1997;Coso et al, 1996;Igishi et al, 1998). The M 2 muscarinic receptor for example, has been shown to mediate its activation of MAPK via G ␤␥ using a PI3K-and tyrosine-kinase-dependent signal pathway (Winitz, et al, 1993;Lopez-Ilasaca, et al, 1997;Igishi et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, in many cell types, the G ␤␥ subunit activates MAPK in a pathway that is PI3K-, Ras-, and often tyrosine-kinase-dependent as well (Lopez-Ilasaca et al, 1997;Coso et al, 1996;Igishi et al, 1998). The M 2 muscarinic receptor for example, has been shown to mediate its activation of MAPK via G ␤␥ using a PI3K-and tyrosine-kinase-dependent signal pathway (Winitz, et al, 1993;Lopez-Ilasaca, et al, 1997;Igishi et al, 1998). In the present study, however, the results using inhibitors specific to PI3K (LY294002) and tyrosine-kinases (genistein), suggest that these signaling intermediates do not play a substantial role in muscarinic M 3 receptor-mediated activation of MAPK in astroglial cells.…”

Section: Discussionmentioning

confidence: 99%

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Activation of mitogen‐activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of ethanol

Yagle

Guizzetti

et al. 2001

Glia

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Mitogen-activated protein kinase (MAPK) can be phosphorylated by mitogens binding to G-protein-coupled receptors and is considered a major pathway involved in cell proliferation. In this study, we report on the activation of MAPK by muscarinic acetylcholine receptors in astroglial cells, namely the 1321N1 human astrocytoma cell line, primary rat cortical astrocytes, and fetal human astrocytes. Carbachol caused a rapid and transient phorphorylation of MAPK (ERK1/2) in all cell types, with an increase in MAPK activity, without changing the levels of MAPK proteins. Human astrocytoma cells were used to characterize the effect of carbachol on MAPK. Experiments with M 2 -and M 3 -receptor subtype-selective antagonists, and with pertussis toxin, indicated that the M 3 subtype is responsible for activating MAPK in glial cells. Pretreatment of cells with the protein kinase C (PKC) inhibitor bisindolylmaleimide I, or downregulation of PKC by 24-h treatment with the phorbol ester TPA inhibited carbachol-induced MAPK activation. Additional experiments with PKC ␣-or PKC ⑀-specific compounds indicated that the ⑀ isozyme of PKC is primarily involved in MAPK activation by carbachol. Chelation of calcium also inhibited MAPK activation by carbachol. Two MEK (MAPK kinase) inhibitors inhibited carbacholinduced DNA synthesis but only at concentrations that exceeded those sufficient to block carbachol-induced MAPK activation. Ethanol (Յ200 mM) had no effect on MAPK when present alone and did not affect carbachol-induced MAPK activation under various experimental conditions, although it inhibits carbachol-induced DNA synthesis at low concentrations (10-100 mM). These results suggest that activation of MAPK by carbachol may be necessary but not sufficient for its mitogenic effect in astroglial cells, and that does not represent a target for ethanol-induced inhibition of DNA synthesis elicited by muscarinic receptors. GLIA 35:111-120, 2001.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of mitogen‐activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of ethanol

Yagle

Guizzetti

et al. 2001

Glia

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“…Figure 6A shows that exogenous ephrinB2/CTF2 stimulates tyrosine phosphorylation of ephrinB without affecting the total levels of the protein (lanes 1-3). Furthermore, the ephrinB2/CTF2-induced tyrosine phosphorylation of ephrinB is mediated by Src kinase because pharmacological inhibitors of Src activity or a dominant-negative Src mutant (DN-Src; Igishi and Gutkind, 1998) inhibited the phosphorylation of ephrinB ( Figure 6A). To test whether ephrinB2/CTF2 regulates the g-secretase cleavage of ephrinB2, we transfected ephrinB2-expressing fibroblasts with ephrinB2/CTF2-myc3 to distinguish it from endogenous ephrinB2/CTF2.…”

Section: Ephrinb Ligands Are Cleaved By Mp and Ps1/c-secretasementioning

confidence: 99%

Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

Georgakopoulos¹,

Litterst²,

Ghersi³

et al. 2006

EMBO J

145

178

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Bidirectional signaling triggered by interacting ephrinB receptors (EphB) and ephrinB ligands is crucial for development and function of the vascular and nervous systems. A signaling cascade triggered by this interaction involves activation of Src kinase and phosphorylation of ephrinB. The mechanism, however, by which EphB activates Src in the ephrinB-expressing cells is unknown. Here we show that EphB stimulates a metalloproteinase cleavage of ephrinB2, producing a carboxy-terminal fragment that is further processed by PS1/c-secretase to produce intracellular peptide ephrinB2/CTF2. This peptide binds Src and inhibits its association with inhibitory kinase Csk, allowing autophosphorylation of Src at residue tyr418. EphrinB2/CTF2-activated Src phosphorylates ephrinB2 and inhibits its processing by c-secretase. These data show that the PS1/c-secretase system controls Src activation and ephrinB phosphorylation by regulating production of Src activator ephrinB2/CTF2. Accordingly, csecretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB. PS1 FAD and c-secretase dominant-negative mutants inhibited the EphB-induced cleavage of ephrinB2 and Src autophosphorylation, raising the possibility that FAD mutants interfere with the functions of Src and ephrinB2 in the CNS.

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“…15 Src family kinases play an important role in relaying signals from both G q -and G i -coupled receptors to MAPK. 28 It was shown that activating one of the proteins in this family, p56 lck , led to a time-dependent activation of phosphotransferase activity of the MAPK in T cells. 28 Angiotensin II stimulation was associated with a rapid activation of c-Src and activation of MAPK in vascular smooth muscle cells.…”

Section: Role Of Ptk Mapk and Pkc In Cerebral Vasospasmmentioning

confidence: 99%

“…28 It was shown that activating one of the proteins in this family, p56 lck , led to a time-dependent activation of phosphotransferase activity of the MAPK in T cells. 28 Angiotensin II stimulation was associated with a rapid activation of c-Src and activation of MAPK in vascular smooth muscle cells. 29 PI-3K activation may be upstream of Ras activation, and PI-3K may be involved in the function of Src, Shc, and Grb2.…”

Section: Role Of Ptk Mapk and Pkc In Cerebral Vasospasmmentioning

confidence: 99%

Mechanism of Endothelin-1–Induced Contraction in Rabbit Basilar Artery

Zubkov

Rollins

Parent

et al. 2000

Stroke

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Background and Purpose-Endothelin-1 (ET-1) is suggested to be a major cause of cerebral vasospasm after subarachnoid hemorrhage. However, the mechanism of ET-1-induced contraction in cerebral arteries remains unclear. This study was undertaken to demonstrate the possible role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in ET-1-induced contraction. Methods-PD-98059, damnacanthal, wortmannin, AG-490, genistein, calphostin C, and staurosporine were used to inhibit, or relax, the ET-1-induced contraction of basilar artery, studied with an isometric tension system. Immunoprecipitation of MAPK in ET-1-stimultated rings of basilar artery without or with the above inhibitors was studied with Western blot.

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Tyrosine Kinases of the Src Family Participate in Signaling to MAP Kinase from both Gqand Gi-Coupled Receptors

Cited by 71 publications

References 26 publications

Activation of mitogen‐activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of ethanol

Activation of mitogen‐activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of ethanol

Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling

Mechanism of Endothelin-1–Induced Contraction in Rabbit Basilar Artery

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