The common network linking cancer with metabolic diseases is a pathway centering on the protein kinase AKT. A kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules to specific substrates, a process referred to as phosphorylation. Kinases are used extensively to transmit signals and control complex processes in cells. AKT, also known as Protein Kinase B (PKB), is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration. This pathway is highly conserved among multicellular organisms, including Drosophila melanogaster, Caenorhabditis elegans and mammals. For unicellular organisms, cell growth and division are natural processes following the uptake of nutrients (amino acids and glucose). The main mediator of nutrient sensing is the protein TOR (target of rapamycin). The evolution of multicellular organisms necessitates novel mechanisms to coordinate growth between tissues and to adjust growth according to varying nutrient conditions. Nature solved this problem by developing insulin or insulin-like growth factors and by wiring TOR into the AKT pathway, which senses these growth factors. This controlled cell proliferation is very important. In fact, a ubiquitous property of cancer is uncontrolled cell proliferation is no longer controlled by growth factors.
Ao et al formulated an intrinsic state hypothesis for cancer. They proposed to understand cancer as robust intrinsic state of endogenous molecular cellular network shaped by evolution. In their hypothesis, the molecular and cellular agents, such as oncogenes and suppressor genes, and related growth factors, hormones, cytokines, etc, form a comprehensive nonlinear dynamical network (which includes the AKT pathway). The nonlinear dynamical system has many locally stable steady states with obvious or non-obvious biological functions, and cancer is one of the steady states. This hypothesis is likely to be true and is worthwhile to be tested extensively. However, if the aim is to study multiple phenotypes including cancer, the hypothesis may fail to capture unique characteristics of cancer because most physiologic processes (and thus most phenotypes) are also in the steady state (homeostasis). As far as the present study is concerned, it turns out that cancer is indeed a steady state (which corresponds to full AKT activation), but this same steady state is sometimes shared by the normal phenotype. Therefore the steady state itself is difficult to distinguish cancer from normal. This is because the normal phenotype corresponds to two steady states (one is shared with cancer) for a given insulin amount. This insulin controls the switching between the two steady states.
AKT is involved in cellular survival pathways, by inhibiting apoptotic processes. AKT is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to general tissue growth. Since it can block apoptosis, and thereby promote cell survival, AKT has been implicated as a major factor in many types of cancer. AKT was originally identified as the oncogene in the transforming retrovirus, AKT8. AKT comprises three highly conserved isoforms in mammals, designated AKT 1/PKBα, AKT 2/PKBβ, and AKT 3/PKBγ. Although each isoform is expressed differentially in a tissue-specific manner, they all contain an N-terminal pleckstrin homology (PH) domain, which mediates lipid protein or protein protein interactions, a kinase domain, and a C-terminal regulatory domain.
AKT is activated by a diverse array of growth factors, cytokines, and other physiologic stimuli in a PI3K dependent manner through a multistep process involving both membrane translocation and phosphorylation. PI3K can be activated through various processes. One of which is through the phosphorylated insulin receptor substrate-1 (pIRS1). Binding of the p85 subunit of PI3K to certain tyrosine phosphorylation sites within the cytoplasmic domain of many receptor tyrosine kinases, and soluble tyrosine kinases, such as FAK and Pyk2, specifically targets recruitment and activation of this lipid kinase. Activated PI3K generates phosphatidylinositol trisphosphate (PIP 3), which in turn recruits inactive AKT from the cytosol to the plasma membrane. Here AKT undergoes a large conformational change, making it accessible to phosphorylation at threonine 308 in the activation loop of the kinase domain by phosphoinositide-dependent protein kinase-1 (PDK1). PDK1 is an enzyme that phosphorylates many different kinases at their corresponding activation loop site, thereby serving as a central modulator of multiple kinase pathways. Phosphorylation within the activation loop allows subsequent phosphorylation at serine 473 in the hydrophobic regulatory domain. This phosphorylation event remained a mystery for many years. However, roles for autophosphorylation, PDK2, mammalian target of rapamycin (mTOR), and more recently, DNAPK, have been reported. On the other hand the phosphatase PHLPP has recently been proposed to dephosphorylate S473, protein phosphatase 2A (PP 2A) is known to dephosphorylate T 308. Once phosphorylated at serine 473, AKT remains active even if the threonine 308 site becomes dephosphorylated.
The best-described genetic deficiencies commonly found in human cancer and impinging upon mTOR signaling are mutations in the PTEN gene. PTEN mutations are associated with a spectrum of cancers, including prostate, breast, lung, bladder, melanoma, endometrial, thyroid, brain, renal carcinomas and others, making it one of the most frequently mutated tumor-suppressor genes. PTEN, a lipid phosphatase, counteracts the lipid-kinase activity of class I PI3Ks. Following growth factor stimulation, activated receptor tyrosine kinases, or intermediaries such as the insulin receptor substrates IRS1 and IRS2, recruit PI3K to the membrane. PI3K phosphorylates phosphatidylinositol bisphosphate PIP 2 at the membrane to generate PIP3. PIP3 serves as a docking site for effector proteins with pleckstrin homology (PH) domains, including the AKT and PDK1. In addition to PTEN deletions, amplifications of both PI3K and AKT occur in several cancers. Considering the prevalence of PTEN mutations and aberrantly activated PI3K-AKT signaling in cancer, identifying the associated downstream signaling events that are crucial for tumor progression is an area of intense investigation.