Transcript “ Signal Transduction”?

From Signal Transduction to
Targeted Therapy
(Fall 2010)
Pin Ling (凌 斌), Ph.D.
Department of Microbiology & Immunology, NCKU
ext 5632
[email protected]
Outline

Signaling Transduction
- Definition
- History
Your involvement is the key
- Mechanisms
in this lecture.
- Example

Targeted Therapy
- Mechanisms
- Examples
- Current Trend
to success
What is Signaling Transduction?
• Conversion of a signal from one physical or
chemical form into another.
• The process initiated by recognition a Signal
by a Sensor (receptor, kinase or enzyme) in
the cell, then converting to one or more
cellular responses through a series of signal
transmission.
A simple scheme of signal transduction
Receptors
Signal
Molecules
involved
in this
Q:
Who first
gets the
ideaprocess,
about
Transducers
called
Signaling
Molecules
“ Signal
Transduction”?
Effectors
Fig 15-1 Adopted from Molecular Biology of The Cell
History of signaling transduction
Adopted from Nobelprize.org
Rodbell’s findings
Adopted from Nobelprize.org
Gilman’s findings
Adopted from Nobelprize.org
Current view of GPCR signaling
Adopted from Molecular Cell Biology
A simple scheme of signal transduction
Receptors
Signal
Transducers
Effectors
Fig 15-1 Adopted from Molecular Biology of The Cell
Four types of surface receptors
GPCR
Receptor
w/o Enzyme
Ion Channel
Receptor w/
Enzyme
Adopted from Molecular Cell Biology
Four common second messengers
Adopted from Molecular Cell Biology
cAMP is the first 2nd Messenger
(1st messenger)
(2nd messenger)
Adopted from Nobelprize.org
A simple scheme of signal transduction
Receptors
Signal
Transducers
Effectors
Fig 15-1 Adopted from Molecular Biology of The Cell
Two types of signal transducers
Enzymatic proteins:
Kinase, GTPase,….etc
Non-Enzymatic proteins:
Adaptors, Scaffolds,...etc
Post-Translation Modifications
(PTMs): Phosphorylation…..
Protein-Protein Interactions,
Signalsome Formation
Two major biochemical events
in signal transduction
Examples of enzymatic proteins
Adopted from Molecular Cell Biology
Adaptors in signal transduction
Adopted from Molecular Cell Biology
Ras activation following EGFR signaling
Adopted from Molecular Cell Biology
Ras activates the MAPK/ERK pathway
Adopted from Cell Signaling
A simple scheme of signal transduction
Receptors
Signal
Transducers
Effectors
Fig 15-1 Adopted from Molecular Biology of The Cell
Types of Post-Translation Modifications
Phosphorylation
Methylation
Acetylation
Chemical groups
Ubiquitination
Sumoylation
Small peptides
Palmitoylation
Myristoylation
Lipid groups
Glycosylation
Sugar groups
Features of Post-Translation Modifications
1. Most are Reversible
2. Regulate Protein Activity, Protein Localization,
Protein Interaction,……etc.
3. Focus on “Protein Phosphorylation” today
Protein Phosphorylation
Adopted from Nobelprize.org
Activation of a enzyme by phosphorylation
Mechanism of Phosphorylation by cAPK (PKA)
Adopted from Molecular Cell Biology
Human Kinome
1.
518 protein kinases
2. Tyr & Ser/Thr kinases
3. Involve many processes
4. Dysregulation => diseases
5. Targets for therapy
G. Manning et al., Science. 2002, 298:1912-34.
Examples of kinase-associated diseases
(Charles Swyers, Nature 2004)
Post-translational modifications of
human nucleosomal histones
Modular interaction domains in
signaling transduction
Check more details in BIND database
(Biomolecular Interaction Network Database)
www.bind.ca
(Pawson et al, Science 2003)
Signaling Specificity
Cell. 2004 Jan 23;116(2):191-203.
Specificity in signal transduction: from phosphotyrosine-SH2
domain interactions to complex cellular systems.
Pawson Tony
Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, 600 University Avenue, Toronto, ON
M5G 1X5, Canada. [email protected]
Science 18 April 2003: Vol. 300. no. 5618, pp. 445 – 452
Assembly of Cell Regulatory Systems Through Protein Interaction
Domains
Tony Pawson
1,2*
and Piers Nash
1
1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5,
Canada.
2 Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
* To whom correspondence should be addressed. E-mail: [email protected]
Multiple signaling cascades form signaling networks
Cell. 2000 Oct 13;103(2):193-200.
Approaches to studying signaling networks
M. Synder et al, Curr Opin Cell Biol. 2002 Apr;14(2):173-9.
Trends in Therapies
1. Gene Therapy – genetic diseases,
cancer,…etc
Signaling
Transduction
=> Molecular
Targets
2. Cell Therapy
– degenerative
diseases
=> Targeted
Therapy
(Alzheimer,
Myocardial
disorders….etc)
3. Targeted Therapy – cancer, immune
disorders,…etc
=> Each has its pros and cons.
A simple scheme of signal transduction
Receptors
Signal
Transducers
Dysregulation of signaling
molecules leads to disorders
Effectors
Fig 15-1 Adopted from Molecular Biology of The Cell
Q1: How to do targeted therapy?
Two major biochemical events in signal
transduction:
(1) Post-Translation Modifications: protein
phosphorylation
Molecules designed to block these two
(2) Protein-Protein
Interactions:
biochemical
events ligandreceptor, protein-dimeriztion
Abl, BCR-Abl, &
Chronic Myelogenous Leukemia (CML)
Nat Rev Cancer. 2005 Mar;5(3):172-83.
Leukemogenic signaling of BCR-Abl
Nat Rev Cancer. 2005 Mar;5(3):172-83.
Development of Chronic
Myelogenous Leukemia (CML)
Nat Rev Cancer. 2005 Mar;5(3):172-83.
Gleevec (STI 571, Imatinib): A Small
Molecule with a Big Impact
Mauro, M. J. et al. Oncologist 2001;6:233-238
Figure 1. Schematic representation of the mechanism of action of STI571
Copyright ©2001 AlphaMed Press
Q2: How to deal with drug resistance ?
Some CML patients develop resistance or relapse
to targeting small molecule (Imatinib).
(1) Develop modified drug (2nd generation kinase
inhibitor)
(2) Combination therapy
2nd generation TKI
-Imatinib-like compound
IC 50, lower is better.
J. Cortes et al Blood,
2009
Molecules for targeted therapies
(1) Small molecules: target the ATP binding site or other
regions in protein kinase domain,
e.g. Gleevec (to BCR-Abl)
(2) Monoclonal Abs: target receptors, cytokines, other
surface proteins,
e.g. Herceptin (to Her), Erbitux (to EGFR)
(3) Others: Decoy receptors (soluble CTLA4-Ig),
Vaccines, RNAi,..etc
Targeting drugs in clinical trials
Ab-mediated signaling inhibition
Adopted from Nature Biotechnology 23, 1147 - 1157 (2005)
Approved mAb
Cancer therapeutics
Summary
1. Signaling transduction is essential for cells to
communicate with environmental stimuli.
2. It usually includes three major components: Receptor,
Transducer, & Effector.
3. Two key biochemical events during signaling
transduction: PTMs & Protein Interactions
4. Dysregulation of signaling molecules perturbs cellular
processes then leading to disease develpoment.
5. Targeted therapy are mostly based on targeting two
biochemical events.
Websites for signaling transduction
Kinase: www.kinase.com (seq, evolution & kinomes)
Protein kinase resource: www.kinasenet.org (kinase
structure)
Alliance for cell signaling: www.signaling-gateway.org
Phosphosite database: www.phosphosite.org (in vivo
phosphorylation sites)
Homework
Gleevec has also been found to effectively treat other
cancer cells such as gastrointestinal stromal tumors
(GIST). However, scientists found no mutation of Abl
kinase in these tumor cells. Please explain the
underlying mechanism of how Gleevec is still working
in this kind of cancer cells even without c-Abl mutation.
2nd generation TKI
STI 571-like compound
B. Druker , Cancer Cell, 2002
Kantarjian et al. Nature Reviews Drug Discovery 5, 717–718 (September 2006) | doi:10.1038/nrd2135