Week 5 Flashcards
What is the PI3-kinase/Akt signalling pathway?
An intracellular signal transduction pathway that promotes metabolism, proliferation, cell survival, growth and angiogenesis in response to extracellular signals
What is the PI3K/Akt/mTOR signaling pathway a regulator for?
Cell growth, protein translation, survival, and metabolism
What does the activation of PI3K/At/mTOR pathway promote?
The survival and proliferation of tumor cells in many human cancers
What are Phosphatidylinositol-4,5-bisphosphate 3-kinases?
Regulatory enzymes involved in the generation of lipid species that modulate cellular signaling pathways through downstream effectors to influence a variety of cellular functions
What are phosphoinositides?
A group of key signaling and structural lipid molecules involved in a myriad of cellular processes
What are PI phosphatases responsible?
The conversion of PIs between distinctive phosphorylation states
What are PI phosphatases?
A large collection of enzymes that are evolved from at least two disparate ancestors. One group is distantly related to endonucleases, which applies divalent metal ions for phosphoryl transfer. The other group is related to protein tyrosine phosphatases, which contains a highly conserved active site motif Cys-X5-Arg (CX5R)
What is PI(4,5)P2?
A relatively common anionic lipid that regulates cellular functions by multiple mechanisms
What is a potent signal for cell survival and cell proliferation?
Phosphorylation by phosphoinositide 3-kinase yielding PI(3,4,5)P3
What can PI(4,5)P2 directly bind to?
Integral and peripheral membrane proteins
What is PTEN?
An important tumor suppressor and hydrolyzes PI(3,4,5)P3
What does PI(4,5)P2 enhance?
PTEN association with the plasma membrane and activates its phosphatase activity
What is PI-5-P?
A newly identified phosphoinositide with characteristics of a signaling lipid but no known cellular function
What controls PI-5-P levels?
The type II PI-5-P 4-kinases (PIP4K IIs), a family of kinases that converts PI-5-P into phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2)
What is the PI-5-P pathway an alternative route for?
PI-4,5-P2 synthesis as the bulk of this lipid is generated by the canonical pathway in which phosphatidylinositol-4-phosphate (PI-4-P) is the intermediate
What are the ongoing issues in the recognition of the three different PI3K classes (I, II and III)?
The need for a better understanding of the in vivo complexity of PI3K regulation and cellular functions
What is Activated PI3K Delta Syndrome?
A primary immunodeficiency disease caused by activating mutations in phosphoinositide 3-kinases (PI3Kδ)
What are the activating mutations that cause APDS?
Activating mutations in either the p110δ catalytic or the p85α regulatory subunit of PI3Kδ
How is PI3K activated?
The activation of PI3K typically occurs as a result of directly stimulated via the regulatory subunit bound to the activated receptor or indirectly activated via adapter molecules such as the insulin receptor substrate (IRS) proteins
How do phosphoinositides (PI) signal?
Phosphoinositides are universal signaling entities that regulate cell activities through direct interaction with membrane proteins (e.g., ion channels, GPCRs) or through membrane recruitment of cytosolic proteins containing domains that directly bind phosphoinositides
What do Class I PI3Ks generate?
Two distinct 3-phosphoinositide lipid messengers, PI(3,4,5)P3 (PIP3) and PI(3,4)P2, that recruit signaling effectors such as pleckstrin homology (PH) domain-containing proteins
What has the function of PI3K signalling been attributed to?
PIP3, with PI(3,4)P2 considered an inconsequential byproduct of PIP3 hydrolysis by SHIP phosphatases. However, accumulating evidence has demonstrated that PI(3,4)P2 directs a distinct branch of the PI3K pathway that regulates a variety of cellular processes with relevance to health and disease, such as B cell activation and autoantibody production, insulin sensitivity, neuronal dynamics, endocytosis and cell migration
How is signalling through PI(3,4)P2 negatively regulated?
By inositol polyphosphate 4-phosphatases (INPP4A and INPP4B), which selectively degrade PI(3,4)P2
What are some signaling proteins that specifically bind to PI(3,4)P2?
Tandem PH domain-containing proteins (TAPP1 and TAPP2) and lamellipodin/RAPH1
What is the function of Ptd(4,5)P(2)?
Promote and organize a wide range of cellular functions, including vesicular membrane traffic and cytoskeletal dynamics, by recruiting functional protein complexes to restricted locations in cellular membranes
How is the accumulation of PI[3,4,5]P3 measured?
Using GFP-labeled PH domains
How are phosphoinositides, in
particular PI(3,4,5)P3 signals,
regulated in normal healthy cells?
The 3-phosphatase PTEN,
degrades PI(3,4,5)P3 at the 3-position
and thereby switches off
PI(3,4,5)P3 signalling
How does PTEN counteract PI3K?
The main function of PTEN is to block the PI3K pathway by dephosphorylating phosphatidylinositol (PI) 3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function
What is the relationship between PI(3,4,5)P3 and PH-domain proteins?
PI(3,4,5)P3 recruits PH domain-containing proteins to the plasma membrane and regulates diverse cellular responses. PI3K phosphorylates PI(4,5)P2 to form PI(3,4,5)P3, which recruits PH domain-containing signaling proteins to the plasma membrane.
What is the importance of PI(3,4,5)P3 and PH domain interactions?
PI3K phosphorylates PI(4,5)P2 to form PI(3,4,5)P3, which recruits PH domain-containing signaling proteins to the plasma membrane.
What does PI3K Akt do?
PI3K-Akt Pathway is an intracellular signal transduction pathway that promotes metabolism, proliferation, cell survival, growth and angiogenesis in response to extracellular signals
Is PI3K and Akt the same?
AKT is downstream to PI3K and is inhibited by Ipatasertib
Where does Akt activation occur?
At the plasma membrane of cells in response to growth factor stimulation and local production of the phosphoinositide lipid phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] following phosphoinositide 3-kinase (PI3K) activation
What does Akt regulate?
Critical cellular processes including cell survival and proliferation, glucose metabolism, cell migration, cancer progression and metastasis through phosphorylation of a variety of downstream targets
Where does serine-threonine kinase Akt exerts its anti-apoptotic effects?
Pro-apoptotic Bc1-2 family member Bad, Forkhead transcription factors, and the cyclic AMP response element-binding protein
What is the role of FOXO3a?
Controls Endothelial Cell Viability through Modulation of the Caspase-8 Inhibitor FLIP* FLICE-inhibitory protein (FLIP) is a homolog of caspase-8 that lacks catalytic activity and has been shown to be important in protecting endothelial cells from apoptosis
What are Forkhead box O (FoxO) transcription factors?
Downstream targets of the serine/threonine protein kinase B (PKB)/Akt
What do Akt kinases regulate?
Processes of cellular proliferation and survival
What are the effects of phosphorylation of FoxOs by Akt?
Inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation
How is FoxO signalling regulated?
By their interactions with other intracellular proteins as well as their post-translational modifications such as phosphorylation
What do FoxOs promote?
Cell growth inhibitory and/or apoptosis signaling by either inducing expression of multiple pro-apoptotic members of the Bcl2-family of mitochondria-targeting proteins, stimulating expression of death receptor ligands such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or enhancing levels of various cyclin-dependent kinase inhibitors (CDKIs)
How does Akt promote cell survival?
Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor
What roles do the p53 tumor suppressor protein and the Akt/PKB kinase play?
In the transduction of pro-apoptotic and anti-apoptotic signals, respectively
What has recent evidence shown in terms of mutated PIK3CA gene?
Recent evidences has demonstrated that the PIK3CA gene is mutated in a range of human cancers including: colon, ovary, breast, brain, liver, stomach and lung
What is the comparison/contrast between somatic and inherited cancers?
Somatic cancer genes are more constrained than both cancer and non-cancer hereditary disease genes
What is PIK3CA?
The most frequently mutated oncogene in human cancers
Where are PIK3CA mutations also found beside cancer cells?
Benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS)
How do PIK3CA mutations act in PROS?
As in cancer, PIK3CA mutations in PROS arise postzygotically, but unlike in cancer, these mutations arise during embryonic development, with their timing and location critically influencing the resulting disease phenotype
What are the fundamental molecules of the PI3K/AKT pathway with increased mutation rates in cancer cases leading to aberrant regulation of the pathway?
PIK3CA, AKT1, and PTEN
What is the role of PI3K in cancer?
PI3K are believed to be one of the key therapeutic targets for cancer treatment based on the observation that hyperactivity of PI3K signaling is significantly correlated with human tumor progression, increased tumor microvessel density and enhanced chemotaxis and invasive potential of cancer cells.
What recent discovery has suggested an oncogenic role for enzymes in the PI3K pathway?
Nonrandom somatic mutations in the PIK3CA gene of many human tumors
What is the most common PI3Kα mutation?
E545K, which results in an amino acid substitution of opposite charge
How does Akt cause cancer?
AKT contributes to impaired apoptosis and cell cycle progression in cancer cells via inhibition of Bad and caspase 9, as well as the phosphorylation of mouse double minute 2 homolog (Mdm2), leading to p53 ubiquitination
What can PTEN genetic mutations cause?
The growth of noncancerous tumors called hamartomas. Hamartomas can show up throughout the body. The mutation can also lead to the development of cancerous tumors
What is PTEN?
An essential tumor suppressor that functions as a lipid phosphatase to negatively regulate phosphatidylinositol 3 kinase/AKT signaling. It also acts as a dual specificity protein phosphatase22, but this activity of PTEN is less well-studied and understood
What is the dysregulation of mTOR/Akt/PI3K signalling pathway associated with?
Genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers
What has the development of targeted therapies against mTOR led to?
The approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers
What happens if kinase PI3K is inhibited?
Inhibition of PI3K can result in both decreased cellular proliferation and increased cellular death
