Akt, also known as protein kinase B, is a signaling protein that plays a key role in many cellular processes, including cell growth, proliferation, and survival. It is activated by a variety of stimuli, including growth factors, hormones, and stress signals, and it functions by phosphorylating (adding a phosphate group to) a variety of downstream proteins, which leads to changes in their activity.
Akt Signaling
The Akt signaling pathway is activated when Akt is phosphorylated on two specific residues, Thr308 and Ser473, by enzymes called phosphoinositide 3-kinases (PI3Ks). Phosphorylation of Thr308 is necessary for the full activation of Akt, while phosphorylation of Ser473 is required for its maximal activity.
Once activated, Akt can phosphorylate a wide range of downstream proteins, including transcription factors, cytoskeletal proteins, and enzymes involved in metabolism. This leads to a variety of downstream effects, including increased protein synthesis, enhanced cell survival, and decreased apoptosis (cell death).
Akt is regulated at multiple levels. It is activated by PI3Ks, which are activated by various stimuli, such as growth factors and hormones. Akt is also regulated by a variety of other proteins, including enzymes that phosphorylate or dephosphorylate Akt, and proteins that bind to and inhibit Akt.
Akt signaling is important in many physiological processes, including cell growth, proliferation, and survival. Dysregulation of Akt signaling has been linked to a variety of diseases, including cancer, diabetes, and cardiovascular disease. Inhibitors of Akt signaling are being developed as potential therapies for these diseases.
In conclusion, Akt is a signaling protein that plays a key role in many cellular processes. It is activated by PI3Ks and functions by phosphorylating downstream proteins. Akt signaling is regulated at multiple levels and is important in many physiological processes. Dysregulation of Akt signaling has been linked to a variety of diseases, and inhibitors of Akt signaling are being developed as potential therapies.
Mechanism of Akt Signaling
The Akt signaling pathway, also known as the PI3K-Akt pathway, is a signaling cascade that regulates various cellular processes such as cell growth, survival, and metabolism. Here are the main steps in the mechanism of Akt signaling:
- The pathway is activated by growth factors, such as insulin or insulin-like growth factor 1 (IGF-1), binding to their respective receptors on the cell surface.
- This binding leads to the activation of a class of enzymes called phosphoinositide 3-kinases (PI3Ks), which phosphorylate a lipid called phosphatidylinositol 4,5-bisphosphate (PIP2) to form phosphatidylinositol 3,4,5-trisphosphate (PIP3).
- PIP3 then recruits Akt, also known as protein kinase B (PKB), to the cell membrane via its binding to pleckstrin homology (PH) domains on the Akt protein.
- Once recruited to the membrane, Akt is activated by phosphorylation at a specific site by a protein called PDK1.
- Activated Akt can then phosphorylate and regulate a variety of downstream targets, including mTOR, GSK3, and various transcription factors to promote cell growth, survival, and metabolism.
- Akt also can inactivate the FOXO family of transcription factors by phosphorylating them, leading to inhibition of pro-apoptotic genes and cell-cycle arrest, hence promoting cell survival.
- Akt also can phosphorylate mTOR (mammalian target of rapamycin), leading to activation of the mTORC1 complex which in turn leads to protein synthesis, cell growth, and proliferation.
- In a negative feedback loop, Akt can inhibit the activity of PI3K via phosphorylation and inactivation of the regulatory subunit p85. This helps to fine-tune the duration and strength of the Akt signaling response.
- The Akt signaling pathway is tightly regulated by multiple mechanisms such as phosphatase activity, ubiquitination, and protein degradation.
It is important to notice that the Akt pathway has many crosstalks with other pathways, that may be activated or inhibited by it. The Akt pathway is also a target of many cancer therapies, as its activation is linked to cancer progression.
Regulation of Akt Signaling
Akt signaling is regulated at several levels, including the activation of Akt itself, the phosphorylation and regulation of downstream targets, and the degradation of Akt and its regulatory proteins.
Activation of Akt: Akt is activated by phosphorylation on specific residues within the activation loop, which is mediated by PDK1 and PDK2. PDK1 and PDK2 are activated by phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is produced by the action of class I phosphoinositide 3-kinases (PI3Ks) on phosphatidylinositol 4,5-bisphosphate (PIP2). PI3Ks are activated by growth factors and other stimuli that bind to cell surface receptors, leading to the activation of Akt and downstream signaling pathways.
Phosphorylation and regulation of downstream targets: Once activated, Akt can phosphorylate and regulate a variety of downstream targets, including transcription factors, cytoskeletal proteins, and enzymes involved in metabolism. For example, Akt can phosphorylate and inhibit the pro-apoptotic protein BAD, leading to the promotion of cell survival.
Degradation of Akt and regulatory proteins: The activity of Akt is also regulated by its degradation. Akt can be targeted for degradation by the ubiquitin-proteasome system, and its stability is regulated by proteins such as PTEN and SHIP1, which inhibit PI3K signaling and prevent the production of PIP3.
Overall, Akt signaling is tightly regulated by a complex network of signaling pathways and regulatory proteins, which allows cells to respond appropriately to changing stimuli and maintain homeostasis. Dysregulation of Akt signaling has been linked to a variety of diseases, including cancer, diabetes, and cardiovascular disease.
Akt Signaling Role in Cancer
Akt signaling plays a critical role in the development and progression of many types of cancer. Activation of the Akt pathway can promote cell survival, growth, and proliferation, as well as inhibit apoptosis (programmed cell death).
In cancer cells, Akt signaling is often activated by mutations or amplifications in the genes encoding PI3K or PTEN, which can lead to excessive Akt activation and downstream signaling. Akt activation can also be caused by overexpression of growth factor receptors or their ligands, leading to inappropriate activation of PI3K and Akt.
Akt signaling has been shown to play a role in the development and progression of many types of cancer, including breast, ovarian, pancreatic, and prostate cancer. Inhibitors of Akt signaling, such as GSK2141795 and MK-2206, are being developed as potential cancer therapies. However, targeting Akt signaling can also have negative effects, as Akt plays a role in maintaining normal physiological processes such as glucose metabolism, and inhibiting Akt signaling can lead to adverse side effects.
FAQs on Akt Signaling
Question 1: What is Another name for Akt?
Answer:
Another name for Akt is protein kinase B (PKB). It is so named because it is a member of the serine/threonine protein kinase family and is the second member (B) of this family to be discovered. The first one is called PKA (protein kinase A). The Akt name is an acronym of the word “RAC-alpha serine/threonine-protein kinase”, an early name of the protein because of the gene from which it was first isolated, RAC-PK-alpha.
Question 2: How is Akt Activated?
Answer:
Akt is activated by phosphorylation on specific residues within the activation loop, which is mediated by PDK1 and PDK2. PDK1 and PDK2 are activated by phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is produced by the action of class I phosphoinositide 3-kinases (PI3Ks) on phosphatidylinositol 4,5-bisphosphate (PIP2). PI3Ks are activated by growth factors and other stimuli that bind to cell surface receptors.
Question 3: What are some downstream targets of Akt?
Answer:
Some downstream targets of Akt include the mammalian target of rapamycin (mTOR), transcription factors, cytoskeletal proteins, and enzymes involved in metabolism.
Question 4: What Enzyme is AKT?
Answer:
Akt, also known as protein kinase B (PKB), is a serine/threonine protein kinase, an enzyme that catalyzes the transfer of a phosphate group from ATP to a specific serine or threonine residue in a target protein.
Question 5: What does PI3K Akt stand for?
Answer:
PI3K is an enzyme that helps to regulate cell growth and survival by converting a molecule called phosphatidylinositol-4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 then acts as a second messenger to activate downstream signaling pathways, including the Akt/mTOR pathway.
Question 6: What does the Akt mTOR pathway do?
Answer:
The Akt/mTOR pathway is a signaling pathway that plays a critical role in regulating cell growth and metabolism. The pathway is activated by growth factors such as insulin, and it controls the activity of mTOR (mechanistic target of rapamycin), a protein that promotes cell growth and proliferation.