Signal Transduction and PI3K Pathway: L16

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Questions and Answers

Which lipid is generated by the activation of PI3K in the signaling pathway discussed?

PtdIns3P

PtdIns4P

PtdIns(4,5)P2

PtdIns(3,4,5)P3 (correct)

What regulates the activity of PI3K as indicated in the provided information?

Only RTK

Only GPCR

RTK and GPCR receptor signaling (correct)

None of the above

What is the precursor lipid for the production of PtdIns(3,4,5)P3?

PtdIns3P

PtdIns(3,4)P2

PtdIns(4,5)P2 (correct)

PtdIns4P

What is the role of Middle T in the context of PI3K signaling?

It regulates PI3K activity along with RTK and GPCR. Signup and view all the answers

What is the relationship between Agonist sensitivity and PtdIns(3,4,5)P3 synthesis?

Agonist sensitivity relates to the stimulation of PI3K. Signup and view all the answers

What role does ligand binding play in the function of catalytic receptors?

It induces internal changes through dimerisation of the receptor. Signup and view all the answers

What type of residues do the protein kinases in catalytic receptors specifically phosphorylate?

Tyrosine residues Signup and view all the answers

What is the outcome of ligand binding to a receptor tyrosine kinase?

Dimerisation leading to cross-phosphorylation. Signup and view all the answers

Which of the following activities is NOT associated with ligand-induced activation of receptor tyrosine kinases?

Inhibition of autophosphorylation. Signup and view all the answers

Which part of a catalytic receptor is subjected to autophosphorylation following ligand binding?

The tyrosine kinase domain. Signup and view all the answers

What is the significance of dimerisation in receptor tyrosine kinases?

It facilitates signal transduction into the cell. Signup and view all the answers

What is a result of ligand-induced conformational changes in receptor tyrosine kinases?

Enhanced phosphorylation of the receptor tail. Signup and view all the answers

What initiates the activation of the protein kinase in a catalytic receptor?

Ligand binding to the receptor. Signup and view all the answers

What is the primary role of receptor mediated tyrosine phosphorylation in the context of adaptor proteins?

To recruit adaptor proteins for downstream signaling Signup and view all the answers

Which adaptor protein is specifically associated with FGFRS1?

GAB1 Signup and view all the answers

How does tyrosine phosphorylation impact receptor internalization?

It promotes receptor ubiquitination and internalization Signup and view all the answers

What is the function of Cbl in relation to tyrosine phosphorylation?

It couples tyrosine phosphorylation to ubiquitination Signup and view all the answers

What does the activation of PI3K in RTK signaling relate to?

Promotion of migration, proliferation, and metabolism Signup and view all the answers

What is Middle T antigen's role in polyoma virus infection?

It activates a PI-kinase necessary for transformation Signup and view all the answers

Which of the following best describes how receptor phosphorylation affects adaptor proteins?

It leads to the phosphorylation and modification of adaptor proteins Signup and view all the answers

What type of proteins are implicated as substrates when signaling occurs through FGFRS1?

Protein kinases and other growth factor receptors Signup and view all the answers

What role does PTEN play in relation to PtdIns(3,4,5)P3?

It removes the 3 phosphate from PtdIns(3,4,5)P3. Signup and view all the answers

Which enzyme is responsible for removing the 5 phosphate from PtdIns(3,4,5)P3?

SHIP1/2 Signup and view all the answers

What effect does the interaction of p110 and p85 have?

It allows recruitment of the holoenzyme to an activated RTK. Signup and view all the answers

Which of the following best describes the primary function of Class 1A PI3K?

It is regulated by RTK activation. Signup and view all the answers

Why is PTEN often deleted or mutated in human tumors?

It acts as a tumor suppressor. Signup and view all the answers

What lipid is generated by the action of SHIP1/2 on PtdIns(3,4,5)P3?

PtdIns(3,4)P2 Signup and view all the answers

Which of the following enzymes balances the actions of PTEN and SHIP1/2?

PI3-Kinase Signup and view all the answers

What is the primary consequence of SHIP1/2's activity on signaling pathways?

It generates new lipid messengers. Signup and view all the answers

What initiates downstream signaling by interacting and recruiting proteins to the membrane?

PtdIns(3,4,5)P3 Signup and view all the answers

Which motif is essential for the interaction of proteins with PtdIns(3,4,5)P3?

PH domain Signup and view all the answers

Which signaling pathway is coupled with the activation of PKB/AKT?

Insulin signaling pathway Signup and view all the answers

What effect does the activation of PKB/AKT have on glucose uptake?

Reduces glycogen synthesis Signup and view all the answers

What is the role of PTEN in the signaling pathway described?

Dephosphorylates PtdIns(3,4,5)P3 Signup and view all the answers

Which component is responsible for translocating Glut4 in the cell?

PKB/AKT Signup and view all the answers

What is the effect of PtdIns(3,4,5)P3 in relation to insulin signaling?

Stimulates protein phosphorylation Signup and view all the answers

Which of the following is NOT a downstream effect of PKB/AKT activation?

Enhanced glycogen synthesis Signup and view all the answers

Which signaling event does PDK1 facilitate in the PKB/AKT pathway?

Phosphorylation of PKB/AKT at T308 Signup and view all the answers

What is the relationship between PKB/AKT and mTORC2?

PKB/AKT activates mTORC2 Signup and view all the answers

What is the role of mTORC1 complex in cellular processes?

It controls protein synthesis. Signup and view all the answers

Which factor primarily controls the RHEB protein involved in mTORC1 activity?

TSC1-TSC2 complex Signup and view all the answers

What is the main substrate of mTORC2?

AKT/PKB kinase Signup and view all the answers

Which protein is responsible for the inhibition of gluconeogenesis in the liver?

Insulin Signup and view all the answers

Which receptors are involved in driving PtdIns(3,4,5)P3 synthesis?

All of the above Signup and view all the answers

What consequence is associated with deregulation of the PI3K/PtdIns(3,4,5)P3 pathway?

Tumor development Signup and view all the answers

What is the function of PTEN in the context of tumor suppression?

Inhibits PtdIns(3,4,5)P3 synthesis Signup and view all the answers

Which protein family does PLC belong to?

Phospholipases Signup and view all the answers

What is the main regulatory action of GSK?

Inhibit glycogen synthesis Signup and view all the answers

Which of the following is primarily stimulated by PDGF in fibroblasts?

Cell proliferation Signup and view all the answers

Study Notes

Glucagon and Insulin Regulation of Glucose Release

Glucagon and insulin antagonistically regulate glucose release in the liver.
During the "fed state," amino acids and glucose are present.
Glucagon triggers glycogen breakdown in the liver, releasing glucose.
Insulin inhibits glycogen breakdown and promotes glucose uptake.

Insulin Receptor Structure and Function

Insulin receptor is a tyrosine kinase receptor.
It includes cysteine-rich, disulfide bond, tyrosine kinase, and immunoglobulin-like domains.
The receptor is involved in cell proliferation, differentiation, and migration, and plays a critical role in development and tissue homeostasis.
Various growth factors function via tyrosine kinase receptors.

Examples of Growth Factors and their Activities

PDGF: Promotes proliferation of connective tissue, glial, and smooth muscle cells. Two different protein chains form three distinct dimer forms (AA, AB, and BB).
EGF: Promotes mesenchymal, glial and epithelial cell proliferation.
TGF: May be important for healing.
FGF: Promotes proliferation of many cells and inhibits some stem cells.
NGF: Promotes neurite outgrowth and neural cell survival.
IGF-I and IGF-II: Promotes proliferation of various cell types, predominantly of fetal origin.

Tyrosine Kinase Receptor Family Characteristics

Transmembrane proteins.
Catalytic receptors
Ligand binding site outside the cell
Intracellular protein kinase active site.
Protein kinase is specific for phosphorylating tyrosine residues.
Ligand binding activates the protein kinase, leading to autophosphorylation of tyrosine residues.

Tyrosine Phosphorylation

Tyrosine phosphorylation is a crucial cellular process.
Middle T antigen plays a vital role in driving cell transformation.
Specific kinases are required for this process.

Dimerization of Ligand-Bound Receptor Tyrosine Kinases

Dimerization of ligand-bound receptor tyrosine kinases is a common mechanism for signaling.
Ligand binding in extracellular domains mediates long-range conformational changes inducing intracellular signalling.
Dimerization is difficult for ligand binding, to induce long-range conformational change in single pass membrane.

Ligand-Induced Dimerization of Tyrosine Kinase Receptors

Ligand-induced dimerization of tyrosine kinase receptors increases kinase activity causing further receptor tail phosphorylation.
Ligand-dependent receptor interactions (TRKA) occurs without external interaction.
Receptor-dependent interactions (IGF-1R).

Activation-Loop Phosphorylation of Insulin Receptor Tyrosine Kinase

Activation loop phosphorylation stabilizes the active conformation of the insulin receptor tyrosine kinase.
The activation loop occludes the active site.
Tyrosine phosphorylation of specific residues (1162, 1163, and 1158) disrupts interactions and induces new ones with other arginine residues (1155, 1164), changing the activation loop's conformation.

SH2 Domain Binding to Tyrosine Phosphorylated Residues

SH2 domains bind to tyrosine-phosphorylated residues, generating a simple output system for describing tyrosine kinase signaling.
SH2 domains are present in approximately 100 proteins.
SH2 domains interact with phosphorylated residues, forming a compact structure with binding pockets.
The number of PTB proteins is found in the human genome, interacting with non-phosphorylated tyrosines.

Different SH2 Domains and Tyrosine Phosphorylated Peptides

Different SH2 domains interact with different tyrosine-phosphorylated peptides.
Specificity is determined by two conserved binding pockets.

Tyrosine Phosphorylation and Intracellular Receptor Domains

Tyrosine phosphorylation of intracellular receptor domains drives the direct interaction and regulation of downstream signaling proteins (e,g kinases, or other proteins).
Examples of these signaling pathways include the PI3K pathway and the RAS pathway
PI3K is recruited by its SH2 domain to the receptor.

Receptors and Receptor-Mediated Tyrosine Phosphorylation

Some receptors use recruitment of adaptor proteins.
FGFRS, GAB1, and IRS1 are examples of receptors.
This step is necessary for further downstream signalling.

Tyrosine Phosphorylation Inducing Receptor Ubiquitination and Internalization

Tyrosine phosphorylation coupled to ubiquitination leads to receptor internalization through the SH2 domain.
Clb protein and Casitas B-lineage (CBL) are proteins involved in downstream signalling after ubiquitination.
Pathways involved might include lysosomal degradation.

RTK Signaling to PI3K

RTK signaling pathways converge on PI3K and related proteins triggering a series of downstream targets.
PLC and RAS are examples of downstream targets, affecting cellular functions including migration, proliferation, and metabolism.

Polyomavirus Interaction with PI-Kinase

Middle T antigen of the polymoma virus interacts with and activates PI kinase.
Middle T associates with tyrosine kinase (pp60cSrc).
A PtdIns-Kinase activity is associated with middle T immunoprecipitates.

PI3K Pathway Regulation

The PI3K pathway is regulated by RTK and GPCR receptor signaling.
PtdIns(3,4,5)P is a lipid second messenger.

Controlling PtdIns(3,4,5)P3 Signal

PTEN is a human tumor suppressor that removes the 3 phosphate from PtdIns(3,4,5)P3.
SHIP removes the 5 phosphate from PtdIns(3,4,5)P3.
These enzymes affect the balance of the signal, important for downstream regulation.

Class 1A PI3K Regulation by RTK Activation

Class 1A PI3K is directly regulated by RTK activation.
Interaction of p110 and p85 subunits affects P110 subunit activity.

Tyrosine Kinase Receptors and Class 1A PI3K

Tyrosine kinase receptors couple to class 1A PI3K through the interaction of the SH2 domain of p85.
This interaction utilizes a specific tyrosine-phosphorylated receptor peptide motif.

PtdIns(3,4,5)P3 Controls Signaling

PtdIns(3,4,5)P3 regulates downstream signaling by recruiting proteins with specific binding domains.
Over 400 proteins interact with phosphoinositides and about 50 interact specifically with PtdIns(3,4,5)P3.
These proteins are involved in cytoskeletal dynamics, vesicle trafficking, and nuclear functions.

PH Domain as Phosphoinositide Sensing Module

PH domains sense phosphoinositides and mediate protein-protein interactions, contributing to dimerization and signaling regulation.
PH domains are found in proteins such as PLCδ1 and Akt.
These domains have a recognizable sequence with multiple Beta sheet structures.

SH2 Domain Mediated Activation of PI3 Kinase

SH2 domain-mediated activation of PI3 Kinase drives PIP3 synthesis and downstream signaling.
IRS1 interacts with PI3K through SH2 interaction.

Activation of PtdIns(3,4,5)P3 Reader PKB/AKT

PtdIns(3,4,5)P3 activation activates PKB/AKT protein kinases and thus affects downstream targets
Examples of target pathways include Glycogen synthesis, fatty acid and triglyceride and protein synthesis.

Receptor-Coupled PtdIns(3,4,5)P3 Synthesis in Different Tissues

PtdIns(3,4,5)P3 synthesis drives tissue-specific downstream signalling in cells responding to insulin, PDGF.
Different tissues display variable responses to PtdIns(3,4,5)P3 synthesis and signalling.

Receptors Driving PIP3 Synthesis and Signaling

Various receptors (GPCRs, tyrosine kinases, immune receptors, TGF receptors, integrins, cytokine receptors) drive PIP3 synthesis and downstream signaling.
Proteins (kinases, phosphatases, GTPases), cytoskeletal proteins are involved in downstream processes including proliferation, apoptosis, membrane trafficking and metabolism.

Deregulation of the PI3K/PtdIns(3,4,5)P3 Pathway in Tumour Development

PI3K/PtdIns(3,4,5)P3 pathway deregulation is a common event in tumour development.
Mutations in PTEN are frequently found in tumors altering the pathway.
Tyrosine kinase receptor overexpression or mutations are also involved.

RTK-Mediated PLC Activation

RTK activation triggers PLC signaling cascades.
PLC activation leads to cellular responses including: migration, proliferation and metabolism.

Phospholipase C Family

The phospholipase C family is characterized by a core structure including a PH domain, EF domains, a split TIM barrel (X and Y), and C2 domain.
The active site has an inhibitory loop, which when removed, inhibits the enzyme.

SH2-Mediated PLC Recruitment and Tyrosine Phosphorylation

SH2 domain of PLC is crucial for its recruitment to RTK receptors.
Tyrosine phosphorylation at specific sites (Y783 and 1253) are necessary for PLC activation.

RTK Activation of RAS Signaling

RTK activation of RAS pathway triggers intracellular signaling cascades and has a role in cell processes including: migration, proliferation, and metabolism.

RAS Signaling Family

RAS signaling family comprises highly homologous isoforms (H-RAS, N-RAS, and K-RAS).
The isoforms are associated with specific tissues and have similar function.
Different isoforms of KRAS are implicated in different types of cancer.

RAS Signaling in Health and Cancers

RAS signaling plays crucial roles in normal cellular processes and in cancer development.
RAS is a highly mutated oncogene protein in human cancers.
RAS mutation affects GTP hydrolysis and may drive cell proliferation and cancer development.

Deregulation of RAS Signaling in Human Tumors

Deregulation of RAS signaling in human tumors drives cell proliferation.
Mutations in the RAS protein or in genes regulating RAS function are frequently implicated in tumor development.
This includes mutations in RAS itself and mutations in regulatory genes such as SOS.

Structural Analysis of RAS Mutations

Structural analysis reveals why mutations in Gln61 and Gly12 in RAS lead to GTP accumulation.
These mutations affect the RAS protein structure affecting GTP hydrolysis activities, leading to its accumulation and downstream oncogenic effects.

Supplementary Slide: SH2 Domain Containing Proteins

This slide describes numerous proteins containing SH2 domains, highlighting their widespread involvement in cellular processes.

Cross Talk with PI3K Pathway and Full Activation of PLC

Cross talk between the PI3K and PLC pathways drives full activation of receptor PLC and the breakdown of PtdIns(4,5)P2.
The results in the regulation of cellular processes

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Description

Test your knowledge on the PI3K signaling pathway and its components. This quiz covers key concepts such as lipid generation, receptor activation, and the role of specific proteins involved in signal transduction. Dive deeper into the mechanisms of receptor tyrosine kinases and understand their functions.