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Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression.

New DC, Wong YH - J Mol Signal (2007)

Bottom Line: When stimulated these receptors modulate the activity of a wide range of intracellular signalling pathways that facilitate the ordered development, growth and reproduction of the organism.There is now a growing body of evidence examining the mechanisms by which G protein-coupled receptors are able to regulate the expression, activity, localization and stability of cell cycle regulatory proteins that either promote or inhibit the initiation of DNA synthesis.In this review, we will detail the intracellular pathways that mediate the G protein-coupled receptor regulation of cellular proliferation, specifically the progression from the G1 phase to the S phase of the cell cycle.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, the Molecular Neuroscience Center, and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clearwater Bay, Hong Kong, China. dnew@ust.hk

ABSTRACT
G protein-coupled receptors are key regulators of cellular communication, mediating the efficient coordination of a cell's responses to extracellular stimuli. When stimulated these receptors modulate the activity of a wide range of intracellular signalling pathways that facilitate the ordered development, growth and reproduction of the organism. There is now a growing body of evidence examining the mechanisms by which G protein-coupled receptors are able to regulate the expression, activity, localization and stability of cell cycle regulatory proteins that either promote or inhibit the initiation of DNA synthesis. In this review, we will detail the intracellular pathways that mediate the G protein-coupled receptor regulation of cellular proliferation, specifically the progression from the G1 phase to the S phase of the cell cycle.

No MeSH data available.


Related in: MedlinePlus

GPCR-mediated activation of MAPKs is also regulated by the generation of intracellular messengers. GPCR activity leads to the activation of AC/cAMP and PLCβ/PKC second messenger pathways. cAMP directly, or via PKA, activates RAP-1/B-Raf/ERK pathways, and potentially inhibits Raf-1 activated ERK activity. The Gαq/PLCβ/PKC pathway promotes Ras/Raf-1/ERK activity, and it is likely that Gq- and Gi/o-coupled GPCRs can activate JNKs and p38. The result of the interplay between these pathways is either proliferative or antiproliferative, depending on the expression of GPCRs and signalling intermediates. Dashed indicators identify the probable involvement of multiple, unidentified intermediates.
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Figure 3: GPCR-mediated activation of MAPKs is also regulated by the generation of intracellular messengers. GPCR activity leads to the activation of AC/cAMP and PLCβ/PKC second messenger pathways. cAMP directly, or via PKA, activates RAP-1/B-Raf/ERK pathways, and potentially inhibits Raf-1 activated ERK activity. The Gαq/PLCβ/PKC pathway promotes Ras/Raf-1/ERK activity, and it is likely that Gq- and Gi/o-coupled GPCRs can activate JNKs and p38. The result of the interplay between these pathways is either proliferative or antiproliferative, depending on the expression of GPCRs and signalling intermediates. Dashed indicators identify the probable involvement of multiple, unidentified intermediates.

Mentions: GPCRs can also promote the MAPK-dependent transcription of cell cycle proteins without transactivating RTKs [33]. Mitogenic pathways activated by different Gα families have been described in detail. Angiotensin II promotes DNA synthesis and proliferation in many cell types by activating the Gq-coupled AT1 receptor. AT1 receptor activity in human adrenal cells induces Ras-dependent ERK activity, leading to increased levels of c-Fos and c-Jun transcription factors and increases in cyclin D1 promoter activity, cyclin D1 protein levels and pRB hyperphosphorylation (Fig. 3 and [48]). Other mitogenic GPCRs, including M1 muscarinic and α1B-adrenergic and purinergic receptors, induce ERK activity via the Ras-independent PKC phosphorylation and activation of Raf-1 [34,49]. However, there are reports of GPCRs using seemingly similar ERK pathways to promote G1 phase arrest. For example, several of the Gi/o-coupled somatostatin receptors inhibit cell cycle progression in a variety of cell types by promoting accumulation of the CDK inhibitors p27Kip1 and p21Cip1 (Fig. 3 and [50]).


Molecular mechanisms mediating the G protein-coupled receptor regulation of cell cycle progression.

New DC, Wong YH - J Mol Signal (2007)

GPCR-mediated activation of MAPKs is also regulated by the generation of intracellular messengers. GPCR activity leads to the activation of AC/cAMP and PLCβ/PKC second messenger pathways. cAMP directly, or via PKA, activates RAP-1/B-Raf/ERK pathways, and potentially inhibits Raf-1 activated ERK activity. The Gαq/PLCβ/PKC pathway promotes Ras/Raf-1/ERK activity, and it is likely that Gq- and Gi/o-coupled GPCRs can activate JNKs and p38. The result of the interplay between these pathways is either proliferative or antiproliferative, depending on the expression of GPCRs and signalling intermediates. Dashed indicators identify the probable involvement of multiple, unidentified intermediates.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1808056&req=5

Figure 3: GPCR-mediated activation of MAPKs is also regulated by the generation of intracellular messengers. GPCR activity leads to the activation of AC/cAMP and PLCβ/PKC second messenger pathways. cAMP directly, or via PKA, activates RAP-1/B-Raf/ERK pathways, and potentially inhibits Raf-1 activated ERK activity. The Gαq/PLCβ/PKC pathway promotes Ras/Raf-1/ERK activity, and it is likely that Gq- and Gi/o-coupled GPCRs can activate JNKs and p38. The result of the interplay between these pathways is either proliferative or antiproliferative, depending on the expression of GPCRs and signalling intermediates. Dashed indicators identify the probable involvement of multiple, unidentified intermediates.
Mentions: GPCRs can also promote the MAPK-dependent transcription of cell cycle proteins without transactivating RTKs [33]. Mitogenic pathways activated by different Gα families have been described in detail. Angiotensin II promotes DNA synthesis and proliferation in many cell types by activating the Gq-coupled AT1 receptor. AT1 receptor activity in human adrenal cells induces Ras-dependent ERK activity, leading to increased levels of c-Fos and c-Jun transcription factors and increases in cyclin D1 promoter activity, cyclin D1 protein levels and pRB hyperphosphorylation (Fig. 3 and [48]). Other mitogenic GPCRs, including M1 muscarinic and α1B-adrenergic and purinergic receptors, induce ERK activity via the Ras-independent PKC phosphorylation and activation of Raf-1 [34,49]. However, there are reports of GPCRs using seemingly similar ERK pathways to promote G1 phase arrest. For example, several of the Gi/o-coupled somatostatin receptors inhibit cell cycle progression in a variety of cell types by promoting accumulation of the CDK inhibitors p27Kip1 and p21Cip1 (Fig. 3 and [50]).

Bottom Line: When stimulated these receptors modulate the activity of a wide range of intracellular signalling pathways that facilitate the ordered development, growth and reproduction of the organism.There is now a growing body of evidence examining the mechanisms by which G protein-coupled receptors are able to regulate the expression, activity, localization and stability of cell cycle regulatory proteins that either promote or inhibit the initiation of DNA synthesis.In this review, we will detail the intracellular pathways that mediate the G protein-coupled receptor regulation of cellular proliferation, specifically the progression from the G1 phase to the S phase of the cell cycle.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, the Molecular Neuroscience Center, and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Clearwater Bay, Hong Kong, China. dnew@ust.hk

ABSTRACT
G protein-coupled receptors are key regulators of cellular communication, mediating the efficient coordination of a cell's responses to extracellular stimuli. When stimulated these receptors modulate the activity of a wide range of intracellular signalling pathways that facilitate the ordered development, growth and reproduction of the organism. There is now a growing body of evidence examining the mechanisms by which G protein-coupled receptors are able to regulate the expression, activity, localization and stability of cell cycle regulatory proteins that either promote or inhibit the initiation of DNA synthesis. In this review, we will detail the intracellular pathways that mediate the G protein-coupled receptor regulation of cellular proliferation, specifically the progression from the G1 phase to the S phase of the cell cycle.

No MeSH data available.


Related in: MedlinePlus