Lecture of Cell Signaling-I Dec. 7, 2004 Contact information: Tzu-Ching Meng Lab 614, IBC, Academia...
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Transcript of Lecture of Cell Signaling-I Dec. 7, 2004 Contact information: Tzu-Ching Meng Lab 614, IBC, Academia...
Lecture of Cell Signaling-I
Dec. 7, 2004
Contact information:Tzu-Ching MengLab 614, IBC, Academia SinicaTel: 27855696 ext 6140Email: [email protected]
Phosphorylation is reversible
Y
Protein
YPP
P
Y
Protein
Y
PY
P
Y
P
PTPs
PTKs
Protein modules inthe control of intracellularsignaling pathways
Docking proteins functionas platforms for the recruitmentof signaling molecules
Models for activation ofSignaling proteins
A). By membrane translocation
B). By conformational change
C). By tyrosine phosphorylation
Signaling pathways activated by receptortyrosine kinases
Mechanisms for attenuationof receptor tyrosine kinases
Classification of human receptor tyrosine kinases (RPTKs)
Classification of human cytoplasmic protine tyrosine kinases
Activation of receptor tyrosine kinases
Juxtamembrane region
Substrate precluding loop
Substrate accessible loop
N-terminal kinase lobe
C-terminal tail
Activation of c-Src
Two modes of intrinsic inhibitionby interactions between:(1) SH2 domain and phosphorylated Y527;(2) SH3 domain and Polyproline region.
Activation of PKB/Akt
PH domain precludesKinase access by PDK-1
*
*
*
*
*
In most cases of CML, the leukemic cells share a chromosome abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal translocation between one chromosome 9 and one chromosome 22. This translocation is designated t(9;22). It results in one chromosome 9 longer than normal and one chromosome 22 shorter than normal. The latter is called the Philadelphia chromosome and designated Ph1.
Expression of afusion PTKp210 Brc-Abl
RetinaldehydeBinding protein-like
PTP1BTCPTP
SHP1 SHP2
MEG2
PESTLyPTP
PTPH1 MEG1PTPD1PTPD2
PTPBAS
CD45
PTPPTPPTPPTP
LARPTPPTP
PTPPTP
PTPPTP
PTPDEP1SAP1
GLEPP1
PEST
SH2
SH2
FERM
FNFNFNFNFNFNFNFNFNFNFNFNFNFNFNFN
FNFNFNFN
FNFN
FN
MAM
Receptor-type PTPsNon-transmembrane PTPs
FNFNFNFNFNFNFNFNFN
‘Classical’ pTyr Specific PTPs (HCSAGxGRxG)
VHRVH1
MKP-1MKP-2MKP-3MKP-4MKP-5
Dual Specificity Phosphatases (HCxxGxxR)
VHR-like
PTEN
Cdc25
The Protein Tyrosine Phosphatase Superfamily (HCx5R)
FYVE-DSP
PTEN(MMAC1)
Cdc25ACdc25BCdc25C
FYVE
KAP(Cdi1)
C2
FN
MAM
Merpin/A5/domain
FERMPTP domain
Src Homology domain 2
PDZ domain
PEST-like
FERM domain
SH2
PEST
Fibronectin IIILike repeat
Immuno-globulin-like
Cadherin-like
Carbonic anhydrase-like
Heavily glycosylated
FYVE
DSP domain
FYVE-domain
C2 Lipid binding domain
Tonks NK & Neel BG, Curr Opin Cell Biol. 2001, 13(2):182-95
Classification of Protein Tyrosine Phosphatases
Non-transmembrane PTPs Receptor-like PTPs
Andersen et al., Mol Cell Biol, 21, 7117, 2001
C-terminal- ER targeting- Proteolytic cleavageProline rich segment- SH3 binding sitesAlternative splicing- Nucleus vs Cytoplasmic
Functional Diversity Through Targeting and Regulatory Domains
SH2 domains- Plasma membrane signaling complexes- Auto-inhibition
Cellular retinaldehyde binding protein-like- Golgi targeting- Secretory vesicles
- Putative lipid-binding domain
FERM domain- Subcellular targeting (e.g. cytoskeletal proteins) PDZ domain(s)- Protein-Protein interactions
PEST domain- Protein-Protein InteractionsBRO1 domain- Functionally uncharacterised; (Found in a number of signal transduction proteins) - Vesicle associatedHis-domain- Functionally uncharacterised
Sequence comparison of human PTP domains
PxxVHCSAGxGRTG
(M9)
WPDxGxP(M8)
IVMxT (M6) KCxxYWP (M7)
TxxDFWxMxW
(M5)
DxxRVxL(M2)DYINA
(M3)NxxKNRY
(M1)
IAxQGP(M4)
QTxxQYxF(M10)
Location of conserved motifs in 3D
http://ptp.cshl.edu
Conserved fold of PTP domains
N-terminal
Central -helixAndersen et al Mol. Cell. Biol. 2001
Protein Tyrosine Phosphatase 1B
WPD loop
PTP Catalytic Mechanism
RetinaldehydeBinding protein-like
PTP1BTCPTP
SHP1 SHP2
MEG2
PESTLyPTP
PTPH1 MEG1PTPD1PTPD2
PTPBAS
CD45
PTPPTPPTPPTP
LARPTPPTP
PTPPTP
PTPPTP
PTPDEP1SAP1
GLEPP1
PEST
SH2
SH2
FERM
FNFNFNFNFNFNFNFNFNFNFNFNFNFNFNFN
FNFNFNFN
FNFN
FN
MAM
Receptor-type PTPsNon-transmembrane PTPs
FNFNFNFNFNFNFNFNFN
‘Classical’ pTyr Specific PTPs (HCSAGxGRxG)
VHRVH1
MKP-1MKP-2MKP-3MKP-4MKP-5
Dual Specificity Phosphatases (HCxxGxxR)
VHR-like
PTEN
Cdc25
The Protein Tyrosine Phosphatase Superfamily (HCx5R)
FYVE-DSP
PTEN(MMAC1)
Cdc25ACdc25BCdc25C
FYVE
KAP(Cdi1)
C2
FN
MAM
Merpin/A5/domain
FERMPTP domain
Src Homology domain 2
PDZ domain
PEST-like
FERM domain
SH2
PEST
Fibronectin IIILike repeat
Immuno-globulin-like
Cadherin-like
Carbonic anhydrase-like
Heavily glycosylated
FYVE
DSP domain
FYVE-domain
C2 Lipid binding domain
Tonks NK & Neel BG, Curr Opin Cell Biol. 2001, 13(2):182-95
Sequence alignment of amino acid residues at phosphatase motif among human DSPs
Amino acid sequence homologies of human DSPs
Catalytic mechanism of DSPs
Mammalian MAP kinase cascades
MAPK and SAPK pathway in mammalian cells
T-x-Y at the activation loop
Function of MAP Kinase Phosphatases (MKPs)
Localisation Inducible Substrate specificity
MKP1 Nuclear Growth factors,
Stress
ERKs=JNKs=p38
MKP2 Nuclear NGFEGF
ERKs>JNKs>>p38
MKP3 Cytosolic No ERKs>>>JNKs=p38
MKP4 Cytosolic ERKs>>JNKs=p38
MKP5 ERK6
PAC-1 Nuclear Mitogen ERKs>p38>>JNKs
hVH-5 Cytosolic JNKs>p38>>>>ERKs
Pyst2 Cytosolic No
VHR No ERK1,ERK2
B23 Nuclear StressMitogen
Mechanism of action of MAP kinase phosphatases (MKPs)
Inactivation of MAP kinases (ERK) by threonine or tyrosine dephosphorylation
The mammalian MAP kinase phosphatases (MPKs)
PTPs and Cancer
Refinement of PTP chromosomal positionsallows for genetic disease linkage studies
19 PTP chromosomal regions are frequently deleted in human cancers
3 PTP chromosomal regions are frequently duplicated in human cancers
PTEN Tumor Suppressor Mutated in various human cancers. Cowden disease
DEP1 Tumor suppressor Colon cancer susceptibility locus Scc1 (QTL in mice)
PTP Tumor Suppressor Primary CNS lymphomas
SHP2 Noonan Syndrome Developmental disorder affecting 1:2500 newbornStomach Ulcers Target of Helicobacter pylori
Cdc25 Cell Cycle Control Target of Myc and overexpressed in primary breast cancer
PRL-3 Metastasis Upregulated in metastases of colon cancer
FAP-1 Apoptosis Upregulated in cancers, inhibits CD95-mediated apoptosis
PTPs and Cancer
PTPs as Drug Targets
PTPs
Diabetes& Obesity
Cancer
Autoimmunity& Allergy
Immunosupression
Infectiousdiseases
Epilepsy
P
P
PTK
(Inactive)
PTK
(Active)
S
(Active)
S
(Inactive)
Autophosphorylation
PTP
PTP
P
P
Interactions Between PTKs and PTP– (1)PTPs function as NEGATIVE Regulators
of Signal Transduction
S
(Inactive)
S
(Active)
PTK
PTP
P
P
Interactions Between PTKs and PTPs—(2)PTPs function as POSITIVE Regulators of
Signal Transduction
Important references
1. Hunter, T. (2000) Signaling-2000 and beyond. Cell, 100: 113-1272. J. Schlessinger (2000) Cell signaling by receptor tyrosine kinases. Cell, 103: 211-2253. Myers, M. et al. (2001) TYK2 and JAK2 are substrates of protein tyrosine phosphatase 1B. J. Biol. Chem., 276: 47771-477744. Andersen, J. N. et al. (2001) Structural and evolutional relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol., 21: 7117-71365. Tonks, N. K. (2003) PTP1B: From the sidelines to the front lines. FEBS Letters, 546: 140-148
Additional references
1. Blume-Jensen, P. Hunter, T. (2000) Oncogenic kinase signaling. Cell, 100: 113-127.
2. Palka, H., Park, M. and Tonks, N.K. (2003) Hepatocyte growth factorreceptor kinase Met is a substrate of the receptor protein tyrosine phosphatase DEP-1. J. Biol. Chem., 278: 5728-5735.
3. Salmeen, A. et al. (2000) Molecular basis for the dephosphorylationof the activation segment of the insulin receptor by protein tyrosinephosphatase 1B. Mol. Cell, 6: 1404-1412.
4. Meng, T.C. et al (2004) Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B. J. Biol. Chem., 279: 37716-37725.