Ras-Raf-MAPK, mTOR-PI3K-AKT信号通路详解
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Signal Transduction Pathways & the Clinical Implications
Lixin KAN, Ph D
Professor Distinguished professor Adjunct professor Anhui Medical University, China Bengbu Medical College, China Northwestern University, USA
Types of signal molecules— Lipid-soluble molecules Water-soluble molecules Gaseous molecules (NO)
Properties of signal molecules— Specificity, highly efficient, competitive Dosage-dependent, saturable Reversible, can be deactivated
The bound protein stimulates the transcription of the gene into mRNA.
4
5 The mRNA is
translated into a specific protein.
Other features: Signal Flow is not always in 1-1 fashion
Motility
Death
Transformation
Cell signaling affects virtually EVERY ASPECT of cell structures and functions.
COMPONENTS
1. Extracellular signal molecules: Ligand/Agonist. 2. Receptor –are specific proteins, which are able to recognize and bind to corresponding ligands. Binding is specific, but not always in 1-1 fashion. 3. Transducers – carries the message from the receptor to the effector. Transducers could be enzymes, adaptor, or others. Transduction is a multi-step process. 4. Effector proteins – produces a 2nd messenger such as cAMP.
1
The steroid hormone testosterone passes through the plasma membrane.
Testosterone, and other lipid soluble factors, such as RA, travels through the blood and enters cells throughout the body. In the cytoplasm, they bind and activate receptor proteins. These activated proteins enter the nucleus and turn on target genes .
Distribution:
• Cell surface receptors • Intracellular receptors
Domains of cell surface receptors:
• The extracellular segment---binding site • The hydrophobic membrane spanning segment--- Transmembrane （ highly conserved） • The cytoplasmic segment---enzyme domain（ highly conserved），transferring a phosphate group from ATP to tyrosine or serine/threonine on a substrate protein.
2. Transmit a message into the cell, which normally leads to a specific cellular effect
3. Each cell has multiple specific receptors, making it responsive to different chemicals.
Signal molecules
Ligand/Agonist
Proteins and peptides:
Hormones, cytokines
Bind to Amino acid derivatives: membrane Catecholamine receptors Chemical Signal Extracellular molecules Physical Signal
most water-soluble molecules/factors bind to cell membrane receptors and activate the signaling transduction pathway.
Signaling pathway via nuclear receptor
l-kan@northwestern.edu
CONTENT
1. Overview: Concept, components, common features of cell signal transduction pathways 2. Ras-Raf-MAPK pathway 3. PI3K/AKT/mTOR pathway 4. Jak-STAT pathway 5. NF-kB pathway 6. Notch pathway 7. Abnormal Cell signaling and diseases
OVERVIEW
Definition
Signal transduction refers to the process that the extracellular stimuli regulate the biological functions, through membranous or intracellular receptors mediated signal cascade.
3. conserved intracellular proteins play key roles in different signaling pathways.
4. different signaling pathways are re-used inห้องสมุดไป่ตู้different contexts.
5. Amplification of external signals is often necessary. 6. Convergence, divergence, and crosstalk among different signaling pathways. 7. Desensitization of receptors.
2. Receptor proteins –are specific proteins, which are able to recognize and bind to corresponding ligands, and transduce signal to next signaling molecules inside of the cell. 1. act as cell’s ‘letter boxes’, and receive messages
Effector protein
common features of cell signaling
1. Receptors could either be cell membrane or nuclear receptors.
2. a relatively small number of mechanisms have been employed.
Schematic view of Cell signaling
Signals
Growth factors Cytokines Extracellular matrix proteins Cell stresses
Biochemical processes
Proliferation
Differentiation
Intracellular proteins
Different Kinds of intracellular proteins serve different purposes
1. 2. 3. 4. 5. 6. 7. 8.
Relay proteins Messenger proteins Adaptor proteins Amplifier proteins Transducer proteins Bifurcation proteins Integrator proteins Latent gene regulatory proteins
Effector protein– produces a mobile second messenger such as cAMP. In the case of cAMP, the effector protein is adenylate cyclase (also called adenylyl cyclase).
Ligand-Receptor binding is an reversible equilibrium process, obeying the law of mass
Receptors Properties:
• • • • Specificity Saturability High affinity Reversibility
Signal Receptor Transducer
Targets
Response
SIGNALS MAY HAVE CONTEXT-DEPENDENT EFFECTS
8. External signals induce two direct cellular responses: (1) changes the activity of pre-existed proteins (2) changes in gene expression.
cell membrane receptors
Testosterone binds to a receptor protein in the cytoplasm, activating it.
2
The hormonereceptor complex enters the nucleus and binds to specific genes.
3
Fatty acid derivatives:
Prostaglandins
Bind to intracellular-- Steroid hormones, Thyroxine , VD3 receptors light, wave, voice, pressure & temperature
1. Extracellular signal molecules: Ligand/Agonist are normally released by signal-producing cells, reach and bind to the receptor protein of target cells.
Lixin KAN, Ph D
Professor Distinguished professor Adjunct professor Anhui Medical University, China Bengbu Medical College, China Northwestern University, USA
Types of signal molecules— Lipid-soluble molecules Water-soluble molecules Gaseous molecules (NO)
Properties of signal molecules— Specificity, highly efficient, competitive Dosage-dependent, saturable Reversible, can be deactivated
The bound protein stimulates the transcription of the gene into mRNA.
4
5 The mRNA is
translated into a specific protein.
Other features: Signal Flow is not always in 1-1 fashion
Motility
Death
Transformation
Cell signaling affects virtually EVERY ASPECT of cell structures and functions.
COMPONENTS
1. Extracellular signal molecules: Ligand/Agonist. 2. Receptor –are specific proteins, which are able to recognize and bind to corresponding ligands. Binding is specific, but not always in 1-1 fashion. 3. Transducers – carries the message from the receptor to the effector. Transducers could be enzymes, adaptor, or others. Transduction is a multi-step process. 4. Effector proteins – produces a 2nd messenger such as cAMP.
1
The steroid hormone testosterone passes through the plasma membrane.
Testosterone, and other lipid soluble factors, such as RA, travels through the blood and enters cells throughout the body. In the cytoplasm, they bind and activate receptor proteins. These activated proteins enter the nucleus and turn on target genes .
Distribution:
• Cell surface receptors • Intracellular receptors
Domains of cell surface receptors:
• The extracellular segment---binding site • The hydrophobic membrane spanning segment--- Transmembrane （ highly conserved） • The cytoplasmic segment---enzyme domain（ highly conserved），transferring a phosphate group from ATP to tyrosine or serine/threonine on a substrate protein.
2. Transmit a message into the cell, which normally leads to a specific cellular effect
3. Each cell has multiple specific receptors, making it responsive to different chemicals.
Signal molecules
Ligand/Agonist
Proteins and peptides:
Hormones, cytokines
Bind to Amino acid derivatives: membrane Catecholamine receptors Chemical Signal Extracellular molecules Physical Signal
most water-soluble molecules/factors bind to cell membrane receptors and activate the signaling transduction pathway.
Signaling pathway via nuclear receptor
l-kan@northwestern.edu
CONTENT
1. Overview: Concept, components, common features of cell signal transduction pathways 2. Ras-Raf-MAPK pathway 3. PI3K/AKT/mTOR pathway 4. Jak-STAT pathway 5. NF-kB pathway 6. Notch pathway 7. Abnormal Cell signaling and diseases
OVERVIEW
Definition
Signal transduction refers to the process that the extracellular stimuli regulate the biological functions, through membranous or intracellular receptors mediated signal cascade.
3. conserved intracellular proteins play key roles in different signaling pathways.
4. different signaling pathways are re-used inห้องสมุดไป่ตู้different contexts.
5. Amplification of external signals is often necessary. 6. Convergence, divergence, and crosstalk among different signaling pathways. 7. Desensitization of receptors.
2. Receptor proteins –are specific proteins, which are able to recognize and bind to corresponding ligands, and transduce signal to next signaling molecules inside of the cell. 1. act as cell’s ‘letter boxes’, and receive messages
Effector protein
common features of cell signaling
1. Receptors could either be cell membrane or nuclear receptors.
2. a relatively small number of mechanisms have been employed.
Schematic view of Cell signaling
Signals
Growth factors Cytokines Extracellular matrix proteins Cell stresses
Biochemical processes
Proliferation
Differentiation
Intracellular proteins
Different Kinds of intracellular proteins serve different purposes
1. 2. 3. 4. 5. 6. 7. 8.
Relay proteins Messenger proteins Adaptor proteins Amplifier proteins Transducer proteins Bifurcation proteins Integrator proteins Latent gene regulatory proteins
Effector protein– produces a mobile second messenger such as cAMP. In the case of cAMP, the effector protein is adenylate cyclase (also called adenylyl cyclase).
Ligand-Receptor binding is an reversible equilibrium process, obeying the law of mass
Receptors Properties:
• • • • Specificity Saturability High affinity Reversibility
Signal Receptor Transducer
Targets
Response
SIGNALS MAY HAVE CONTEXT-DEPENDENT EFFECTS
8. External signals induce two direct cellular responses: (1) changes the activity of pre-existed proteins (2) changes in gene expression.
cell membrane receptors
Testosterone binds to a receptor protein in the cytoplasm, activating it.
2
The hormonereceptor complex enters the nucleus and binds to specific genes.
3
Fatty acid derivatives:
Prostaglandins
Bind to intracellular-- Steroid hormones, Thyroxine , VD3 receptors light, wave, voice, pressure & temperature
1. Extracellular signal molecules: Ligand/Agonist are normally released by signal-producing cells, reach and bind to the receptor protein of target cells.