G protein‐coupled receptor‐induced Akt activity in cellular proliferation and apoptosis

Abstract

Akt, also known as protein kinase B (PKB), is a serine ⁄ threonine protein kinase that plays a pivotal role in many physiological processes, including metabolism, development, cell cycle progression, migration and survival [1][2][3][4]. The Akt subfamily of protein kinases consists of three isoforms -Akt1, Akt2 and Akt3 (also termed PKBa, PKBb and PKBc) -which are the products of distinct genes. All three proteins share a conserved tertiary structure of an N-terminal pleckstrin homology domain, a kinase domain and a C-terminal regulatory domain containing the hydrophobic motif phosphorylation site [5]. While the homology between the three isoforms allows for a degree of functional redundancy [1], there also seems to be considerable scope for isoform-specific activation and substrate specificity [3,6].Akt plays an integral role in the phosphoinositide 3-kinase (PI3K) signaling pathways. PI3K pathways are activated in response to extracellular signals mediated by cell-surface receptors of the G protein-coupled receptor (GPCR), integrin and growth factor ⁄ receptor tyrosine kinase (RTK) superfamilies. Receptor-mediated activation of PI3K results in the generation of phosphatidylinositol (3,4,5)-trisphosphate from phosphatidylinositol (4,5)-bisphosphate, a reaction that is reversed by the enzymes phosphatase and tensin homologue (PTEN) and SH2-domain-containing inositol polyphosphate 5-phosphatase (SHIP). Both Akt and

Gq Protein-induced Apoptosis Is Mediated by AKT Kinase Inhibition That Leads to Protein Kinase C-induced c-Jun N-terminal Kinase Activation

“…Studies using G q knock-out in mice demonstrated a role of this protein in platelet activation as well as in the development and functioning of the central nervous system and the heart (7,8). Other G q PCRregulated effects have been identified by other methods, including regulation of proliferation (9), the reproductive system (10), brain functioning (6), and more (11). Aside from these G q PCRinduced effects, these central receptors were also implicated in growth arrest or apoptosis in few pathological systems (11)(12)(13).…”

“…Among all G proteins, the four members of the G q family (G q , G 11 , G 14 , and G 15/16 ) function primarily via activation of phospholipase C-␤ (6). This effector then produces the second messengers inositol trisphospate and diacylglycerol, which further elevate intracellular calcium levels as well as protein kinase C (PKC) activity to induce many intracellular signaling and the plethora of G q PCR-induced effects.…”

Glycogen Synthase Kinase-3β Is a Functional Modulator of Serotonin-1B Receptors

“…The mechanisms of regulating Akt by 5-HT1BR are not fully understood, but it is believed that both ␣-and ␤␥-subunits of G-protein as well as ␤-arrestin are associated with GPCR-induced activation of Akt (DeWire et al, 2007;New et al, 2007;Yang et al, 2009). The finding that GSK3 influences 5-HT1BR-induced activation of Akt further supports the significant effect of GSK3 in 5-HT1BR-regulated signaling.…”

Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors

“…13) Some G protein-coupled receptors (GPCRs) have been shown to activate the Akt pathway. 14) There are several reports suggesting that the Akt pathway mediates responses to adenosine receptor stimulation: The phosphorylation of Akt and ERK1/2 via the activation of adenosine A 2B receptors regulates the function of glioblastoma stem cells, 15) and the activation of adenosine A 3 receptors induces the activation of Akt in melanoma cells.…”