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Lecture of Cell Signaling-I
Dec. 7, 2004 Contact information: Tzu-Ching Meng Lab 614, IBC, Academia Sinica Tel: ext 6140
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Phosphorylation is reversible
PTPs P P P P Y Y Y Y Protein Protein Y Y P P PTKs
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Protein modules in the control of intracellular signaling pathways Docking proteins function as platforms for the recruitment of signaling molecules
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Models for activation of
Signaling proteins A). By membrane translocation B). By conformational change C). By tyrosine phosphorylation
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Signaling pathways activated by receptor tyrosine kinases Mechanisms for attenuation of receptor tyrosine kinases
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Classification of human receptor tyrosine kinases (RPTKs)
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Classification of human cytoplasmic protine tyrosine kinases
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Activation of receptor tyrosine kinases
Juxtamembrane region N-terminal kinase lobe Substrate precluding loop Substrate accessible loop C-terminal tail
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Activation of c-Src Two modes of intrinsic inhibition
by interactions between: SH2 domain and phosphorylated Y527; (2) SH3 domain and Polyproline region.
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Activation of PKB/Akt PH domain precludes Kinase access by PDK-1
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Expression of a fusion PTK p210 Brc-Abl
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 a fusion PTK p210 Brc-Abl
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The Protein Tyrosine Phosphatase Superfamily (HCx5R)
‘Classical’ pTyr Specific PTPs (HCSAGxGRxG) Dual Specificity Phosphatases (HCxxGxxR) PTEN Non-transmembrane PTPs Receptor-type PTPs VHR-like Cdc25 W FN FN FN FN FN FN FN MAM FN FN W FN FN FERM FN FN C2 FN FN FN FN FN FN FN FN FN SH2 FN FN FYVE SH2 VHR VH1 MKP-1 MKP-2 MKP-3 MKP-4 MKP-5 KAP (Cdi1) FYVE- DSP Cdc25A Cdc25B Cdc25C PTEN (MMAC1) P E S T PTPb DEP1 SAP1 GLEPP1 PTPH1 MEG1 PTPD1 PTPD2 PTPBAS SHP1 SHP2 MEG2 CD45 PTP1B TCPTP PEST LyPTP FERM PTPm PTPk PTPr PTPl LAR PTPs PTPd PTPa PTPe PTPg PTPz PTP domain FERM domain Heavily glycosylated Fibronectin III Like repeat Carbonic anhydrase-like SH2 Src Homology domain 2 FN Cadherin-like DSP domain Retinaldehyde Binding protein-like Merpin/A5/m domain MAM FYVE-domain PEST-like FYVE PEST W Immuno- globulin-like Lipid binding domain PDZ domain C2 Tonks NK & Neel BG, Curr Opin Cell Biol. 2001, 13(2):182-95
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Classification of Protein Tyrosine Phosphatases
Non-transmembrane PTPs Receptor-like PTPs Andersen et al., Mol Cell Biol, 21, 7117, 2001
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Functional Diversity Through Targeting and Regulatory Domains
FERM domain - Subcellular targeting (e.g. cytoskeletal proteins) PDZ domain(s) - Protein-Protein interactions C-terminal - ER targeting - Proteolytic cleavage Proline rich segment - SH3 binding sites Alternative splicing - Nucleus vs Cytoplasmic SH2 domains - Plasma membrane signaling complexes - Auto-inhibition PEST domain - Protein-Protein Interactions BRO1 domain - Functionally uncharacterised; (Found in a number of signal transduction proteins) - Vesicle associated His-domain - Functionally uncharacterised Cellular retinaldehyde binding protein-like - Golgi targeting - Secretory vesicles - Putative lipid-binding domain
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Sequence comparison of human PTP domains
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Location of conserved motifs in 3D
IVMxT (M6) KCxxYWP (M7) WPDxGxP (M8) TxxD FWxMxW (M5) QTxx QYxF (M10) PxxV HCSAGxGRTG (M9) IAxQGP (M4) DxxRVxL (M2) NxxKNRY (M1) DYINA (M3)
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Conserved fold of PTP domains
N-terminal Central a3-helix Andersen et al Mol. Cell. Biol. 2001
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Protein Tyrosine Phosphatase 1B
WPD loop
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PTP Catalytic Mechanism
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The Protein Tyrosine Phosphatase Superfamily (HCx5R)
‘Classical’ pTyr Specific PTPs (HCSAGxGRxG) Dual Specificity Phosphatases (HCxxGxxR) PTEN Non-transmembrane PTPs Receptor-type PTPs VHR-like Cdc25 W FN FN FN FN FN FN FN MAM FN FN W FN FN FERM FN FN C2 FN FN FN FN FN FN FN FN FN SH2 FN FN FYVE SH2 VHR VH1 MKP-1 MKP-2 MKP-3 MKP-4 MKP-5 KAP (Cdi1) FYVE- DSP Cdc25A Cdc25B Cdc25C PTEN (MMAC1) P E S T PTPb DEP1 SAP1 GLEPP1 PTPH1 MEG1 PTPD1 PTPD2 PTPBAS SHP1 SHP2 MEG2 CD45 PTP1B TCPTP PEST LyPTP FERM PTPm PTPk PTPr PTPl LAR PTPs PTPd PTPa PTPe PTPg PTPz PTP domain FERM domain Heavily glycosylated Fibronectin III Like repeat Carbonic anhydrase-like SH2 Src Homology domain 2 FN Cadherin-like DSP domain Retinaldehyde Binding protein-like Merpin/A5/m domain MAM FYVE-domain PEST-like FYVE PEST W Immuno- globulin-like Lipid binding domain PDZ domain C2 Tonks NK & Neel BG, Curr Opin Cell Biol. 2001, 13(2):182-95
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Sequence alignment of amino acid residues at
phosphatase motif among human DSPs
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Amino acid sequence homologies of human DSPs
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Catalytic mechanism of DSPs
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Mammalian MAP kinase cascades
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MAPK and SAPK pathway in mammalian cells
T-x-Y at the activation loop
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Function of MAP Kinase Phosphatases (MKPs)
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Mechanism of action of MAP kinase phosphatases (MKPs)
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Inactivation of MAP kinases (ERK)
by threonine or tyrosine dephosphorylation
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The mammalian MAP kinase phosphatases (MPKs)
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PTPs and Cancer Refinement of PTP chromosomal positions
allows 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
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PTPs and Cancer PTEN Tumor Suppressor Mutated in various human cancers. Cowden disease DEP1 Tumor suppressor Colon cancer susceptibility locus Scc1 (QTL in mice) PTPk Tumor Suppressor Primary CNS lymphomas SHP2 Noonan Syndrome Developmental disorder affecting 1:2500 newborn Stomach 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
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PTPs as Drug Targets Immunosupression Diabetes Autoimmunity & Obesity
& Allergy PTPs Infectious diseases Cancer Epilepsy
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Interactions Between PTKs and PTP– (1)
PTPs function as NEGATIVE Regulators of Signal Transduction S (Inactive) Autophosphorylation PTK (Inactive) (Active) P P PTP S (Active) P P PTP
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Interactions Between PTKs and PTPs—(2)
PTPs function as POSITIVE Regulators of Signal Transduction PTP P P S S (Inactive) (Active) PTK
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Important references Hunter, T. (2000) Signaling-2000 and beyond. Cell, 100: J. Schlessinger (2000) Cell signaling by receptor tyrosine kinases. Cell, 103: 3. Myers, M. et al. (2001) TYK2 and JAK2 are substrates of protein tyrosine phosphatase 1B. J. Biol. Chem., 276: Andersen, J. N. et al. (2001) Structural and evolutional relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol., 21: 5. Tonks, N. K. (2003) PTP1B: From the sidelines to the front lines. FEBS Letters, 546:
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Additional references
Blume-Jensen, P. Hunter, T. (2000) Oncogenic kinase signaling. Cell, 100: 2. Palka, H., Park, M. and Tonks, N.K. (2003) Hepatocyte growth factor receptor kinase Met is a substrate of the receptor protein tyrosine phosphatase DEP-1. J. Biol. Chem., 278: 3. Salmeen, A. et al. (2000) Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol. Cell, 6: 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:
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