Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists

Abstract

Neuropeptides, including mammalian bombesin-like peptides, act as potent cellular growth factors and have been implicated in a variety of normal and abnormal processes, including development, inflammation, and malignant transformation. These signaling peptides exert their characteristic effects on cellular processes by binding to specific G protein-coupled receptors (GPCR) on the surface of their target cells. Typically, the binding of a neuropeptide to its cognate GPCR triggers the activation of multiple signal transduction pathways that act in a synergistic and combinatorial fashion to relay the mitogenic signal to the nucleus and promote cell proliferation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades is an important early response to neuropeptides. An emerging theme in signal transduction is that these agonists also induce rapid and coordinate tyrosine phosphorylation of cellular proteins including the nonreceptor tyrosine kinase p125fak and the adaptor proteins p130cas and paxillin. This tyrosine phosphorylation pathway depends on the integrity of the actin cytoskeleton and requires functional Rho. The purpose of this article is to review recent advances in unraveling the pathways that play a role in transducing mitogenic and migratory responses induced by G protein-coupled neuropeptide receptor agonists.

Differential FAK phosphorylation at Ser-910, Ser-843 and Tyr-397 induced by angiotensin II, LPA and EGF in intestinal epithelial cells

“…Numerous studies have demonstrated that a rapid increase in the tyrosine phosphorylation of the non-receptor tyrosine kinase FAK is a prominent early event in cells stimulated by multiple signaling molecules that regulates cell proliferation, migration, and apoptosis [3,6,52]. On the contrary, much less is known about the regulation of FAK phosphorylation at serine residues by external stimuli including GPCR agonists and growth factors.…”

Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

“…[Ca 2ϩ ] i in IEC-18 cells. The mobilization of Ca 2ϩ from intracellular stores leading to a rapid and transient increase in [Ca 2ϩ ] i is one of the earliest events stimulated by the binding of agonists to GPCRs that signal through G q -mediated activation of PLC (5,20,66). To identify the expression of G q -coupled GPCRs in intestinal epithelial cells, multiple peptide hormones were screened for their ability to induce Ca 2ϩ mobilization in IEC-18 cells, a nontransformed intestinal epithelial cell line derived from rat ileum (56,57 There are at least three GPCR subtypes that bind AVP, namely, V 1A , V 1B , and V 2 receptors (6).…”

“…The two best characterized isoforms, ERK-1 (p44 mapk ) and ERK-2 (p42 mapk ), are directly activated by phosphorylation on specific tyrosine and threonine residues by the dualspecificity ERK kinase (or MAPK kinase; MEK) (83). In some cell types, activation of Pyk2 and Src family kinases triggers the stimulation of the Raf-MEK-ERK cascade via Ras activation (30,66).…”

“…Previous studies demonstrated that the proliferation and migration of these intestinal epithelial cells is regulated by a variety of polypeptide growth factors, including epidermal growth factor (EGF), insulin-like growth factor I, and hepatocyte growth factor, which act via single-pass transmembrane tyrosine kinase receptors (3,17,51). Neuropeptides and vasoactive peptides that signal through G protein-coupled receptors (GPCRs), characterized by seven-transmembrane helices, also act as potent cellular growth factors for a variety of cell types (63,64,66,67). However, the role of GPCRs and their ligands in intestinal epithelial cell signaling and proliferation remains poorly understood.…”

Effect of the addition of diammonium citrate to α-cyano-4-hydroxycinnamic acid (CHCA) matrix for the detection of phosphorylated peptide in phosphorylation reactions using cell and tissue lysates

“…However, the effect depended on substrate concentration. (J Am Soc Mass Spectrom 2007, 18,[1925][1926][1927][1928][1929][1930][1931]) © 2007 American Society for Mass Spectrometry P rotein phosphorylation is one of the most important post-translational modifications, as it regulates cellular functions through information processing [1][2][3]. In this context, the determination of phosphorylated peptides using mass spectrometry has attracted much attention in many biological and pharmacological fields.…”