PI3K-AKT signaling pathway

The PI3K-AKT signaling pathway describes a highly conserved, multi-stage, strictly controlled physiological reaction sequence. In the physiological state of the cell, the PI3K-AKT signaling pathway is controlled by growth factors and chemokines. These bind to receptor tyrosine kinases or G protein-coupled receptors (GPCR) and activate PI3K and induce the conversion of phosphatidylinositol(3,4)-bisphosphate (PIP2) lipids into phosphatidylinositol(3,4,5)-trisphosphate (PIP3) through their catalytic domain.

PKB-AKT binds to PIP3 at the plasma membrane and allows PDK1 to access and phosphorylate T308 in the "activation loop", resulting in partial activation of PKB/Akt. This PKB/AKT modification is sufficient to activate mTORC1 by directly phosphorylating and inactivating the proline-rich Akt substrate of 40 kDa (PRAS40) and tuberous sclerosis protein 2 (TSC2). Activation of AKT leads to additional substrate-specific phosphorylation in both the cytoplasm and the nucleus, including inhibitory phosphorylation of the pro-apoptotic FOXO proteins. Fully active PKB/AKT mediates numerous cellular functions such as angiogenesis, metabolism, growth, proliferation, survival, protein synthesis, transcription and apoptosis. The dephosphorylation of AKT and the conversion of PIP3 to PIP2 by PTEN counteract AKT signaling.

Regulation of activity: Phosphatases play a decisive role in the activation of the PI3K-AKT signaling pathway, leading to the dephosphorylation of proteins and thereby influencing the activity of the signaling molecules, such as the tumor suppressor gene PTEN (Phosphatase and Tensin Homolog deleted on chromosome 10). PTEN is a protein that can perform various functions both in the cytoplasm and in the cell nucleus. Membrane-bound PTEN acts as a phosphatase. The enzyme removes the 3-phosphate from the phosphatidylinositol triphosphate and forms the phosphatidylinositol bisphosphate (Maehama T et al. 1998). In this way, the activity of AKT is controlled and cell proliferation and apoptosis are regulated.

Another regulator of the PI3K/AKT signaling pathway is the phosphatase SHIP (SH2 domain containing inositol 5-phosphatase). This enzyme dephosphorylates PIP3 at the 5-phosphate of the inositol ring and forms the phosphatidylinositol bisphosphate. SHIP-deficient mice show increased Akt activity and can develop myeloproliferative syndromes.

Although PTEN and SHIP reduce PIP3 levels in the cell, the tumor suppressor gene PTEN appears to play a predominant role in this signaling pathway.

In many tumors, the PI3K/AKT pathway is constitutively active. Increased PI3K activity can also be induced by somatic mutations in the PI3K catalytic subunit (p110α). Three common point mutations in the PIK3A gene have been identified. Two are located in the helical domain (E542K and E545K) and one in the kinase domain (H1047R) of the protein (Vogt PK et al. 2007). These mutations have been detected particularly in prostate, endometrial, and colon carcinoma, as well as in breast carcinoma (Chalhoub N et al. 2009). In contrast, PI3K mutations are rare in hematopoietic and lymphoid tissues (Chalhoub N et al 2009).

Inhibition of the PI3K/AKT pathway appears to be a potential therapeutic approach in various tumors. There are now more than 100 compounds in preclinical development that inhibit the PI3K/AKT pathway. An increasing number of these inhibitors are now being investigated in clinical trials. In particular, these are compounds that specifically block the PI3K, AKT and mTOR kinases. The modes of action of these new inhibitors are diverse. Some of these inhibitors have been developed in such a way that several effector kinases are also blocked simultaneously.

The PI3 kinases are lipid kinases and form a large protein family, which are divided into three classes based on their structure, substrate specificity and activation mechanism. They phosphorylate the inositol ring of inositol phospholipids in the plasma membrane, whereby three different products can be formed. Class I is the best characterized form and is further subdivided into type IA and type IB.

The PI3K IA kinases are heterodimers and consist of a p85 regulatory (p85α, p55α, p50α, p85β or p55γ) and a p110 catalytic (p110α, p110β or p110δ) subunit. The p85 unit is encoded by three different genes (PIK3R1, PIK3R2 and PIK3R3), whereby three additional splice variants (p85α, p55α, p50α) of PIK3R1 are known (Engelman JA et al. 2006). The p85α and p85β units are ubiquitously expressed. Expression of the other isoforms is restricted to specific tissues such as muscle, brain and liver. The p110 subunit is encoded by the genes PIK3CA, PIK3CB or PIK3CD. While the p110α and p110β are ubiquitously expressed, the expression of p110δ is restricted to the immune system (Kok K et al. 2009). Activation of PI3K IA occurs via receptor tyrosine kinases or oncogenes. After activation of a receptor tyrosine kinase, PI3K is recruited to the cell membrane.

The PI3K IB kinase is also a heterodimer and consists of the catalytic subunit p110γ and the regulatory subunits p101, p84 or p87. Activation of PI3K occurs exclusively through the interaction between G proteins and GPCR via the Gβγ domain of the regulatory subunit. PI3K IB is particularly expressed in leukocytes, heart, pancreas, liver and skeletal muscle (Patrucco E et al. 2004; Sasaki T et al. 2000).

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