Prolonged Activation of Extracellular Signal-regulated Kinase by a Protein Kinase C-dependent and N17Ras-insensitive Mechanism Mediates the Proliferative Response of Gi/o-coupled Somatostatin sst4 Receptors

Sellers, Lynda A.

doi:10.1074/jbc.274.34.24280

Cited by 27 publications

(18 citation statements)

References 45 publications

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“…However, the lack of effect of LY 294002 on the somatostatin-induced ERK phosphorylation and the ineffectiveness of PD 98059 on Akt and p70 rsk activation suggest that these kinase cascades activated by the sst 2(b) receptor are parallel but distinct. This is in contrast to the cross talk that has been demonstrated between the ERK and PI 3-K pathways for other G-protein-coupled receptors (39,43). Although, ERK and PI 3-K activities are critical for somatostatin to induce a proliferative function in CHOsst 2(b) cells, it ap- 30°C).…”

Section: Discussioncontrasting

confidence: 43%

Receptor Isoforms Mediate Opposing Proliferative Effects through Gβγ-Activated p38 or Akt Pathways

Sellers

Alderton

Carruthers

et al. 2000

Molecular and Cellular Biology

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The opposing effects on proliferation mediated by G-protein-coupled receptor isoforms differing in their COOH termini could be correlated with the abilities of the receptors to differentially activate p38, implicated in apoptotic events, or phosphatidylinositol 3-kinase (PI 3-K), which provides a source of survival signals. These contrasting growth responses of the somatostatin sst 2 receptor isoforms, which couple to identical G␣ subunit pools (G␣ i3 > G␣ i2 >> G␣ 0 ), were both inhibited following ␤␥ sequestration. The sst 2(a) receptormediated ATF-2 activation and inhibition of proliferation induced by basic fibroblast growth factor (bFGF) were dependent on prolonged phosphorylation of p38. In contrast, cell proliferation and the associated transient phosphorylation of Akt and p70 rsk induced by sst 2(b) receptors were blocked by the PI 3-K inhibitor LY 294002. Stimulation with bFGF alone had no effect on the activity of either p38 or Akt but markedly enhanced p38 phosphorylation mediated by sst 2(a) receptors, suggesting that a complex interplay exists between the transduction cascades activated by these distinct receptor types. In addition, although all receptors mediated a sustained activation of extracellular signal-regulated kinases (ERK1 and ERK2), induction of the tumor suppressor p21 cip1 was detected only following amplification of ERK and p38 phosphorylation by concomitant bFGF and sst 2(a) receptor activation. Expression of constitutively active Akt in the presence of a p38 inhibitor enabled a proliferative response to be detected in sst 2(a) receptor-expressing cells. These findings demonstrate that the duration of activation and a critical balance between the mitogen-activated protein kinase and PI 3-K pathways are important for controlling cell proliferation and that the COOH termini of the sst 2 receptor isoforms may determine the selection of appropriate ␤␥-pairings necessary for interaction with distinct kinase cascades.Mitogen-activated protein (MAP) kinases are proline-directed serine/threonine kinases that play important roles as mediators of cellular responses to a variety of stimuli such as growth factors, cytokines, hormones, and environmental stresses (18,23). MAP kinases in mammalian cells have been classified into at least four subfamilies: extracellular signalregulated kinases (ERKs), stress-activated protein kinases/cJun NH 2 -terminal kinase (SAPKs/JNK), p38 kinases, and BMK1/ERK5 (51). ERK is activated by many growth factors and cytokines and is implicated in cell growth as well as differentiation (32). Various stressors such as chemical agents and UV irradiation, tumor necrosis factor, interleukin-1, CD40 ligand, and Fas/CD95 ligand stimulate the activities of SAPKs and p38 (10, 24) which appear to play a decisive role in the control of cell death. Thus, the SAPK pathway is critical during ceramide-induced (49) and stress-induced (56) apoptosis as well as in the Daxx-mediated Fas cascade (55), whereas transfection of a constitutively active mutant of MKK3/6, the physiological ac...

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Section: Discussioncontrasting

confidence: 43%

Receptor Isoforms Mediate Opposing Proliferative Effects through Gβγ-Activated p38 or Akt Pathways

Sellers

Alderton

Carruthers

et al. 2000

Molecular and Cellular Biology

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“…However, although inhibition of Src or Ras attenuated the transient phase of the ERK activity profile, these transduction effectors did not seem necessary for the sustained activation of ERK. This differential requirement for transduction mediators during the time course of ERK activation has also recently been demonstrated for the G i/o -coupled somatostatin sst 4 receptor in which the acute phase is both Src-and Ras-dependent, but the prolonged ERK response is mediated by protein kinase C (50). The mobilization of Ca 2ϩ through the P2Y 1 receptor could account for the stimulation of the Ca 2ϩ -dependent PKC isoforms that have been shown to activate the ERK cascade at the point of Raf (51) and thus through a Ras-independent mechanism.…”

Section: Discussionmentioning

confidence: 97%

Adenosine Nucleotides Acting at the Human P2Y1Receptor Stimulate Mitogen-activated Protein Kinases and Induce Apoptosis

Sellers

Simon

Lundahl

et al. 2001

Journal of Biological Chemistry

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104

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For the widely distributed P2Y receptors for nucleotides, the transductional and functional responses downstream of their coupling to G proteins are poorly characterized. Here we describe apoptotic induction and the associated differential stimulation of mitogenactivated protein (MAP) kinase family members by the human P2Y 1 receptor. The potent P2Y 1 receptor agonist, 2-methylthio-ADP (2-MeSADP), stimulated the extracellular-signal regulated kinases (ERK1/2) (EC 50 ϳ5 nM) as well as several, but not all isoforms detected, of the stress-activated protein kinase (SAPK) family. Phosphoisoforms of p38 were unaffected. The induced kinase activity was blocked by the P2Y 1 receptor-selective antagonist, adenosine-2-phosphate-5-phosphate, but unaffected by pertussis toxin. In addition, the endogenous ligand ADP, and significantly also 2-MeSATP, induced concentration-dependent phosphorylation changes in the same MAP kinase family members. The sustained activation of ERK1/2 was associated with Elk-1 phosphorylation that was abolished by the MEK1 inhibitor, PD 98059. However, the concomitant transient activation of the SAPKs was not sufficient to induce c-Jun or ATF-2 phosphorylation. The transient phase of the ERK activity was partially inhibited either by the phosphatidylinositol 3-kinase inhibitor, LY 294002, or the PKC inhibitor, Gö 6976. In addition, the Src inhibitor, PP1, or expression of dominant negative Ras also attenuated the transient phase of ERK phosphorylation. In contrast, inhibition of Ras or Src had no effect on the sustained ERK activity, which was critically dependent on phosphatidylinositol 3-kinase. The transient SAPK activity was suppressed by expression of a dominant negative form of MKK4. Furthermore, this kinase-deficient mutant inhibited 2-MeSADP-induced caspase-3 stimulation and the associated decrease in cell number. In conclusion, adenosine di-and triphosphate stimulation of the human P2Y 1 receptor can transiently activate the Ras-ERK cascade via the cooperative effects of phosphatidylinositol 3-kinase, Src and PKC. The sustained ERK stimulation, via a Ras-insensitive pathway, culminates in Elk-1 activation without inducing a proliferation effect. The transient SAPK activity did not evoke transcription factor phosphorylation but was required for the P2Y 1 receptor-mediated apoptotic function.Extracellular nucleotides can interact with cell surface P2 receptors both in the central nervous system and in peripheral tissues to produce a broad range of physiological effects. The P2 family is divided into two main types as follows: the P2X receptors are ligand-gated ion channels, and the P2Y receptors are G protein-coupled (1, 2). Part of the present study describes the signaling pathways of the P2Y 1 receptor, the first member of the P2Y family to be identified (3). The P2Y 1 receptor is widely distributed and has been described in mammalian heart, vascular, liver, kidney, prostate, gastrointestinal, pulmonary, connective, and immune tissues (4, 5). It has also been identified in skeletal muscle ...

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“…The identification of PKC isozyme and the precise mechanism for PKC activation remain to be determined. S1P receptors have been shown to regulate non-receptor Srcfamily tyrosine kinase, which functions as a transduction system between G iβγ and Ras-dependent ERK activation (Sellers, 1999). Also, PKC-dependent Src-family tyrosine kinase activation plays a crucial role in tumor necrosis factor-α or 12-Otetradecanoylphorbol-13-acetate-induced COX-2 promoter activity through activating NF-κB (Huang et al, 2003).…”

Section: Discussionmentioning

confidence: 98%

Sphingosine 1-phosphate induces cyclooxygenase-2 via Ca2+-dependent, but MAPK-independent mechanism in rat vascular smooth muscle cells

et al. 2007

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Prolonged Activation of Extracellular Signal-regulated Kinase by a Protein Kinase C-dependent and N17Ras-insensitive Mechanism Mediates the Proliferative Response of Gi/o-coupled Somatostatin sst4 Receptors

Cited by 27 publications

References 45 publications

Receptor Isoforms Mediate Opposing Proliferative Effects through Gβγ-Activated p38 or Akt Pathways

Receptor Isoforms Mediate Opposing Proliferative Effects through Gβγ-Activated p38 or Akt Pathways

Adenosine Nucleotides Acting at the Human P2Y1Receptor Stimulate Mitogen-activated Protein Kinases and Induce Apoptosis

Sphingosine 1-phosphate induces cyclooxygenase-2 via Ca2+-dependent, but MAPK-independent mechanism in rat vascular smooth muscle cells

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