Phospholipases, Small GTPases, and Other Molecules in the Akt Pathway Proteins

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Phospholipases, Small GTPases, and Other Molecules in the Akt Pathway Proteins

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Phospholipases, Small GTPases, and Other Molecules in the Akt Pathway Proteins Background

Phospholipases are ubiquitously expressed enzymes that control the levels of phospholipid substrates by catalysing the lysis of phosphorylated lipids. The released lipid molecules then initiate signalling cascades known to regulate cell function.

This complex family is involved in the mechanisms of a number of diseases including cancer and heart disease, and has been implicated in conditions such as brain disorder/injury, kidney and immune cell dysfunction. There are four distinct classes of phospholipases (PL), identified as PLA, PLB, PLC and PLD, each promoting cleavage at specific ester bonds within phospholipids. Each phospholipase family has several isoforms, which function within specific cell types and are differentially distributed. The PLA class has members A1 and A2. PLA1 specifically hydrolyses the acyl group at the SN-1 position of phospholipids and both extracellular and intracellular PLA1 enzymes are known in mammals. PLA2 cleaves the second carbon group of glycerol to release the fatty acid molecule (Figure 1), and includes both cytosolic and secreted phospholipases. PLA2 is responsible for the release of arachidonic acid from membrane phospholipids. This leads to the formation of eicosanoids, including leukotrienes and prostaglandins, which can affect many potentially pathogenic responses, such as diverse inflammatory/allergic diseases. PLA2 isoforms have also been implicated in neurological disorders. PLA2G6 is involved in regulating levels of phosphatidylcholine and PLA2G6 mutations have been linked with infantile neuroaxonal dystrophy, a progressive neurological disorder that causes intellectual disability and movement problems. PLB cleaves acyl chains from both the sn-1 and sn-2 positions, and so can carry out the reactions of both PLA1 and PLA2. PLCs are only found intracellularly, and cleave phospholipids before the phosphate group, generating diacylglycerol, DAG, and inositol triphosphate (IP3). A wide range of disorders has been associated with PLC genetic aberrations. Mutations in PLCB1 have been linked to a form of epilepsy and changes in the PLCG2 gene are associated with auto-inflammation and antibody deficiency. The development of PLC inhibitors is an active area of research. There are several isoforms of phospholipase D, and these play a central role in numerous physiological processes, including membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, and cell migration. PLD isoforms has been implicated in the pathophysiology of multiple diseases, in particular the progression of Parkinson’s and Alzheimer’s (PLD3), and various cancers (PLD2).

Role of phospholipases in AKT signaling pathway

Phospholipase is an effector of signal transduction, which is equivalent to adenylate cyclase in the cAMP system and is also a membrane integrin. The activity of phospholipase is regulated by the G protein. When the signaling molecule recognizes that the receptor binds, the subunit of the G protein is activated. The activated G-alpha subunit contacts the phospholipase by diffusion and activates the phospholipase. Activated phospholipase hydrolyzes 4,5-diphosphophosphatidylinositol (PIP2) on the plasma membrane to produce IP3 and diacylglycerol DAG. The phosphatidylinositol 3-kinase (PI3Ks) protein family is involved in cell proliferation and differentiation. Regulation of various cellular functions such as apoptosis and glucose transport. Increases in PI3K activity are often associated with a variety of cancers. PI3K phosphorylates the third carbon atom of the inositol ring of the phosphatidylinositol PI (a membrane phospholipid). PI has a smaller proportion in the cell membrane fraction and is less than phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. However, in the brain cell membrane, the content is relatively rich, reaching 10% of the total amount of phospholipids. Phosphatidylinositol PI participates in the classical PI3K-AKT-mTOR signaling pathway.

Small GTPases

Small GTPases are a family of hydrolases that bind to and hydrolyze guanosine triphosphate (GTP). They are a G protein found in the cytosol that is homologous to the alpha subunit of the heterotrimeric G protein, but unlike the alpha subunit of the G protein, small GTPases can act independently as hydrolases. Function to combine and hydrolyze. Guanosine triphosphate (GTP) forms guanosine diphosphate (GDP). The most famous members are Ras GTPases, so they are sometimes referred to as the Ras subfamily GTPase. A typical G protein is active when bound to GTP and is inactive when bound to GDP. Then you can replace GDP with free GTP. Therefore, the G protein can be turned on and off. GTP hydrolysis is accelerated by GTPase activating protein (GAP), while GTP exchange is catalyzed by guanine nucleotide exchange factor (GEF). Activation of GEF typically activates its cognate G protein, whereas activation of GAP results in inactivation of the homologous G protein. The guanosine nucleotide dissociation inhibitor (GDI) maintains a small GTP-enzyme in an inactive state. Small GTPases regulate a variety of processes in cells, including growth, cell differentiation, cell movement, and lipid vesicle trafficking.

Role of Small GTPases in AKT signaling pathway

The small G protein Rheb was first discovered in 1994 and was originally reported to interact with the Raf1 kinase. In 2003, mammalian cell in vitro assays and Drosophila in vivo experiments confirmed that Rheb is a target of TSC1-TSC2, activating mTORC1, thereby affecting the classical PI3K-AKT-mTOR signaling pathway.


1. Wennerberg K.; et al. The Ras superfamily at a glance. Journal of Cell Science. 2005, 118(5):843-846

2. Goitre, L.; et al. The Ras superfamily of small GTPases: the unlocked secrets. Methods in Molecular Biology. 2013, 1120: 1-18

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