G protein mediated signaling pathways in lysophospholipid induced cell proliferation and survival

Abstract

Agonist activation of a subset of G protein coupled receptors (GPCRs) stimulates cell proliferation, mimicking the better known effects of tyrosine kinase growth factors. Cell survival or apoptosis is also regulated via pathways initiated by stimulation of these same GPCRs. This review focuses on aspects of signaling by the lysophospholipid mediators, lysophosphatidic acid (LPA), and sphingosine 1 phosphate (S1P), which make these agonists uniquely capable of modulating cell growth and survival. The general features of GPCR coupling to specific G proteins, downstream effectors and signaling cascades are first reviewed. GPCR coupling to G(i) and Ras/MAPK or to G(q) and phospholipase generated second messengers are insufficient to regulate cell proliferation while G(12/13)/Rho engagement provides additional complementary signals required for cell proliferation. Survival is best predicted by coupling to G(i) pathways that regulate PI3K and Akt, but other signals generated through different G protein pathways are also implicated. The unique ability of LPA and S1P to concomitantly stimulate G(i), G(q), and G(12/13) pathways, given the proper complement of expressed LPA or S1P receptors, allows these receptors to support cell survival and proliferation. In pathophysiological situations, e.g., vascular disease, cancer, brain injury, and inflammation, components of the signaling cascade downstream of lysophospholipid receptors, in particular those involving Ras or Rho, may be altered. In addition, up or downregulation of LPA or S1P receptor subtypes, altering their ratio, and increased availability of the lysophospholipid ligands at sites of injury or inflammation, likely contribute to disease and may be important targets for therapeutic intervention.

Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells

“…Experiments using receptor antagonists point to S1P 1 /S1P 3 being involved. Activation of PI3K and p42/44 MAPK are two pathways known to be activated by S1P (31), with the notion that these pathways also promote cell survival. Kang et al reported up-regulation of cFLIP and phosphorylation of Bad downstream of PI3K/Akt signaling (45).…”

“…Besides, S1P is exported from the cell by members of the ATP-binding cassette transporter family. Once secreted, S1P binds to one of its five G-proteincoupled receptors (S1P 1 -S1P 1 ), activating downstream pathways such as p38 MAPK, p42/44 MAPK, PI3K, c-Jun NH 2 -terminal kinase, or Ca 2+ signaling (29)(30)(31).…”

Lysophosphatidic acid receptors (LPARs): Potential targets for the treatment of neuropathic pain

“…LPA-mediated signalling via Gα 12/13 and activation of the signalling pathways involving RhoA, Rhokinase, ROCK and Ras appear to be involved in NP (Inoue et al, 2004;Radeff-Huang et al, 2004;Ueda, 2006). Inhibition of Rho signalling pathways by Clostridium botulinum C3 exoenzyme (BoTXC3) or the antagonist Y-27632 (see Table 1), prior to peripheral nerve injury, blocks hyperalgesia and nociceptive responses in mice (Ahn et al, 2009;Inoue et al, 2004;Inoue et al, 2006).…”

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

“…Since Edg receptors affect cell motility via the Gi pathway [13,14], we next tested the dependence of gelatinase activity on Gi using its specific inhibitor, PTX. We chose also to evaluate OVCA 429, another EOC cell line that does not invade well through matrigel, as a means of comparison.…”

“…We have recently shown that S1P regulates transcription and surface presentation of its own receptors [12]. The G proteins that mediate the biologic effects of S1P are associated with particular Edg's, and pathways have been identified to all known S1P receptors through coupled G-Proteins, including the Gi subgroup [13]. Further downstream is Rac, a small GTP binding protein of the Rho family.…”