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

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.

Figure 1

Modulation of intracellular cAMP levels by GPCR-coupled mechanisms affects cell cycle progression. Agonist activation of G_s-coupled receptors promotes increased AC activity and cAMP accumulation. Subsequent PKA activation leads to the activation of the transcription factor CREB and the regulation of the expression of cyclins and the CDK inhibitor p27^Kip1. The resulting effect on cell cycle progression is dependent on a number of factors, including the concentration of cAMP generated. PKA can also regulate, positively or negatively, other mitogenic pathways, particularly those leading to the activation of MAPKs, (see text for further details). Activation of the AC/cAMP/PKA axis can be antagonized by the activation of GPCRs coupled to G_i/o-family proteins. However, the definitive involvement of these MAPK and G_i/o-coupled pathways in regulating proliferation has not been established (indicated by dashed lines).

Figure 2

GPCR transactivation of EGFR leads to the activation of multiple mitogenic pathways. GPCR/G protein activity of many families of G protein promotes the activity of MMPs via PLCβ-dependent, or possibly Src-dependent (indicated by dashed lines – see text for further details), mechanisms. MMP activity releases EGF in its soluble form. The resulting EGFR activity promotes the formation of a signalling complex and the activation of PI3K, MAPK and ROCK kinases in a GPCR and cell type specific manner. The increased expression of cyclins promotes progression into S phase, while the upregulation of CDK inhibitors p21^Cip1 and p27^Kip1 delays S phase entry. Dashed lines also identify the probable involvement of multiple, unidentified intermediates in the transcriptional regulation of cell cycle proteins.

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 Gα_q/PLCβ/PKC pathway promotes Ras/Raf-1/ERK activity, and it is likely that G_q- and G_i/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.

Figure 4

Further PKC-dependent cell cycle regulation. G_i/o-, G_s- and G_q-family coupled GPCRs can activate PLCβ and PKC activity via Gα or Gβγ subunits. Activated PKC can phosphorylate and activate PKD, leading to the activity of ERK-dependent proliferative pathways. PKC is also able to initiate a series of events that promotes the transcriptional activity of NF-κB. NF-κB activates the promoter regions of cyclin D1 as well as those of p21^Cip1 and p27^Kip1, causing S phase entry or delay. Dashed indicators identify the probable involvement of multiple, unidentified intermediates.

Figure 5

Src family kinase-dependent cell cycle control. G_q-, G_12/13- and G_i/o-coupled GPCRs are all known to regulate mitogenesis via the transactivation of Src-dependent integrin signalling complexes. G_q- and G_i/o-coupled receptors also utilize Src to activate a variety of MAPK pathways. G_s-, G_i/o- and G_q-coupled receptors promote proliferation via the activation of the STAT transcription factors, and this has been postulated to be Src-dependent (shown in dashed lines). Full STAT activity may require phosphorylation by JAKs and MAPKs. Dashed lines also identify the probable involvement of multiple, unidentified intermediates in the transcriptional regulation of cell cycle proteins.

Figure 6

Activation of PI3K-dependent cell cycle regulation. The expression, stability and activity of cyclins and CDK inhibitors are regulated by the activity of several PI3K-dependent pathways. Numerous GPCRs activate PI3K isoforms either through Gβγ subunits or via RTK and integrin transactivation. PI3Ks activate ERKs and Akt, leading to the transcriptional regulation of p27^Kip1. In addition, Akt phosphorylates p27^Kip1, thereby affecting its nuclear localization. Acting through TSC1, TSC2 and mTOR, Akt can negatively affect the stability of p27^Kip1, although GPCR regulation of proliferation through mTOR has not been established (indicated by dashed lines). PI3Ks may also promote proliferation by promoting cyclin expression (via p70^S6K) and stability (via Akt and GSK3). Dashed lines also identify the probable involvement of multiple, unidentified intermediates in the transcriptional regulation of cell cycle proteins.