ReviewG protein-coupled receptors stimulation and the control of cell migration
Introduction
G protein-coupled receptors (GPCRs) represent the largest family of membrane receptors. Analysis of the human genome has revealed that more than 800 genes encode these 7 trans-membrane receptors. These are activated by a large variety of stimuli ranging from small molecules such as neurotransmitters to larger hormones. The stimulation of GPCRs has been reported to engage a broad range of physiological responses, such as blood pressure regulation, smooth muscle contraction, neurotransmission, chemotaxis, and proliferation. All are important for maintaining homeostasis, but in some cases, disregulation of GPCR function leads to the development of pathological conditions. In this review, we will discuss the molecular mechanisms by which GPCRs control the process of cell migration markedly enhanced in diseases such as cancer and atherosclerosis.
Chemokines are small molecular weight proteins that bind to their cognate receptors to elicit directional migration or chemotaxis. The activation of receptors such as CXCR2 play an important role in leucocyte chemotaxis, wound healing, angiogenesis, and inflammation [1]. All these biological processes require enhanced cellular motility. Disregulation of the function of these chemokine receptors has been linked to several pathologies including chronic inflammation, metastatic progression, and aberrant angiogenesis during tumor progression. Alternatively, activation of CXCR4, another chemokine receptor, plays an important role in hematopoiesis as well as in the development, and organization of the immune system. Increasing evidence suggest an important role for this receptor in different types of cancer of both hematopoietic and nonhematopoietic origins [2]. For example, enhanced CXCR4 expression increases the migratory capacity of non-small cell lung cancer (NSCLC) cells [3]. In addition, it was shown that breast cancer cells typically express high levels of functional CXCR4 receptors that can direct chemotaxis and invasive responses [4]. Treatment with anti-CXCR4 monoclonal antibodies (mAbs) was shown to inhibit the metastatic spread to target organs in vivo [4].
Several bioactive lipids such as Sphingosine 1-phosphate (S1P) also regulate cell migration in different conditions. S1P stimulation enhances motility of endothelial cells [5], while decreasing migration of vascular smooth muscle cells (VSMCs) [6]. Lysophosphatidic acid (LPA), another bioactive lipid, mediates multiple cellular responses, including proliferation, differentiation, motility, and survival in both normal physiological conditions and disease states. Importantly, LPA can mediate many of the āhallmarks of cancerā [7], including angiogenesis, and tissue invasion, two phenomena characterized by enhanced migration [8], [9]. These biological actions, coupled with aberrant receptor expression and elevated production of LPA in malignancies, indicate that LPA is intimately involved in tumor progression. Chen et al. have demonstrated that activation of the LPA1 (EDG2) and LPA2 (EDG4) receptors mediate LPA stimulated migration of breast cancer cells [10].
Hormones like angiotensin II (Ang II) and endothelins (ET) are well known for their effects on the cardiovascular system. Through the stimulation of their receptors (ATR), Ang II stimulates hypertrophy and hyperplasia of VSMCs [11]. This vasoactive peptide was also shown to stimulate VSMC migration, through a different molecular mechanism involving the activation of the MAP kinase pathway [12]. Similarly, ET stimulation also leads to increased migration. For example, activation of ETB receptors promotes activation of intracellular signalling cascades regulating turnover of focal adhesion complexes leading to enhanced motility in endothelial cells [13]. These are only a few examples to illustrate that stimulation of GPCRs can promote reorganization of the actin cytoskeleton and lead to altered motile phenotypes in a broad variety of cells.
Section snippets
Activation of heterotrimeric G proteins
GPCRs classically transmit their signal via the activation of G protein heterotrimer, which contains Ī±, Ī² and Ī³ subunits. Binding of agonists induces reorientation of the tri-dimensional structure of the receptor, which results in GTP loading of the GĪ± subunit. This first signalling event results in reorganization of the G proteins structure and propagation of downstream signalling by both the Ī± and Ī²Ī³ subunits. There are four major families of G proteins: Gs, Gi/o, Gq/11, and G12/13 [14]. All
Rho GTPases
It is well recognized that small GTP-binding proteins of the Rho family are central regulators of the dynamic reorganization of actin-based cytoskeleton and are key mediators of several cellular processes, including cell migration and polarity [38]. These GTPases are highly conserved through species and act as molecular switches to transmit signals from different sources. Like all G proteins, Rho family members are inactive when bound to GDP and become activated upon GTP loading. Guanine
Role of G protein-coupled receptor kinases (GRKs), arrestins and regulators of G protein signalling (RGS) in the control of cell migration
One common characteristic of GPCRs is their ability to initiate their own desensitization. This process mainly serves to prevent sustained coupling to heterotrimeric G proteins upon chronic exposure to stimuli. Following their activation, GPCRs are phosphorylated by specific enzymes such as the G protein-coupled receptor kinases (GRKs). Receptor phosphorylation serves to create high affinity binding sites for the recruitment of Ī²arrestin proteins, which are responsible for desensitization [90].
Transactivation of tyrosine kinase receptors by G protein-coupled receptors, an alternative mechanism leading to cell migration
GPCRs can also diversify their signalization by communicating with and transactivating growth factor receptors. The first evidence of such a cross-talk between these two receptor families came from the observation that MAPK activation and DNA synthesis mediated by endothelin, LPA or thrombin treatments were blocked by a specific EGFR inhibitor [146]. Elucidation of the molecular mechanism demonstrated that EGFR transactivation was dependent upon the activation of metalloproteases of the ADAM
Perspectives
Activation of GPCRs by extracellular stimuli promotes enhanced motile phenotypes for a broad variety of cells. This important biological process results from the activation of numerous signalling cascades involving proteins such as GTPases, kinases and Ī²arrestins. These ultimately act in concert to regulate remodeling of the actin cytoskeleton. In this review, we have focused mainly on the early events activated following the stimulation of GPCRs. Ultimately, these signalling cascades act on
Acknowledgments
This work was supported by the Canadian Institutes of Health Research (CIHR) grant MOP-79470 to AC. AC is the recipient of a New Investigator Award from the CIHR.
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