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Lecture of Cell Signaling-I. Dec. 7, 2004. Contact information: Tzu-Ching Meng Lab 614, IBC, Academia Sinica Tel: 27855696 ext 6140 Email: [email protected] Phosphorylation is reversible. PTPs. P. P. P. P. Y. Y. Y. Y. Protein. Protein. Y. Y. P. P. PTKs.

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Lecture of Cell Signaling-I

Dec. 7, 2004

Contact information:

Tzu-Ching Meng

Lab 614, IBC, Academia Sinica

Tel: 27855696 ext 6140

Email: [email protected]


Phosphorylation is reversible

PTPs

P

P

P

P

Y

Y

Y

Y

Protein

Protein

Y

Y

P

P

PTKs


Protein modules in

the control of intracellular

signaling pathways

Docking proteins function

as platforms for the recruitment

of signaling molecules


Models for activation of

Signaling proteins

A). By membrane translocation

B). By conformational change

C). By tyrosine phosphorylation


Signaling pathways

activated by receptor

tyrosine kinases

Mechanisms for attenuation

of receptor tyrosine kinases




Activation of receptor tyrosine kinases

Juxtamembrane

region

N-terminal

kinase lobe

Substrate precluding

loop

Substrate accessible

loop

C-terminal tail


Activation of c-Src

  • Two modes of intrinsic inhibition

  • by interactions between:

  • SH2 domain and

  • phosphorylated Y527;

  • (2) SH3 domain and

  • Polyproline region.


Activation of PKB/Akt

PH domain precludes

Kinase 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 a

fusion PTK

p210 Brc-Abl


W abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

W

W

W

FN

FN

FN

FN

FN

FN

FN

FN

FN

FERM

SH2

SH2

SH2

W

FERM

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

FN

FN

FN

FN

FN

FN

FN

MAM

FN

FN

FN

C2

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FYVE

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

MEG2

SHP1

SHP2

CD45

PTP1B

TCPTP

PEST

LyPTP

Heavily

glycosylated

PTPm

PTPk

PTPr

PTPl

LAR

PTPs

PTPd

PTPa

PTPe

PTPg

PTPz

FERM

domain

PTP domain

Carbonic

anhydrase-like

Fibronectin III

Like repeat

Src Homology

domain 2

FN

Cadherin-like

DSP domain

Retinaldehyde

Binding protein-like

Merpin/A5/m

domain

MAM

FYVE-domain

FYVE

PEST-like

PEST

Lipid binding

domain

Immuno-

globulin-like

C2

PDZ domain

Tonks NK & Neel BG, Curr Opin Cell Biol. 2001, 13(2):182-95


Classification of Protein Tyrosine Phosphatases abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

Non-transmembrane PTPs

Receptor-like PTPs

Andersen et al., Mol Cell Biol, 21, 7117, 2001


C-terminal abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

- ER targeting

- Proteolytic cleavage

Proline rich segment

- SH3 binding sites

Alternative splicing

- Nucleus vs Cytoplasmic

FERM domain

- Subcellular targeting

(e.g. cytoskeletal proteins)

PDZ domain(s)

- Protein-Protein interactions

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

Functional Diversity Through

Targeting and Regulatory Domains


Sequence comparison of human PTP domains abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


Location of conserved motifs in 3D abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

IVMxT (M6)

KCxxYWP (M7)

WPDxGxP

(M8)

TxxD

FWxMxW

(M5)

QTxx

QYxF

(M10)

PxxV

HCSAGxGRTG

(M9)

IAxQGP

(M4)

DxxRVxL

(M2)

NxxKNRY

(M1)

DYINA

(M3)

http://ptp.cshl.edu


Conserved fold of PTP domains abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

N-terminal

Central a3-helix

Andersen et al Mol. Cell. Biol. 2001


Protein Tyrosine Phosphatase 1B abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

WPD loop


PTP Catalytic Mechanism abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


W abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

W

W

W

FN

FN

FN

FN

FN

FN

FN

FN

FN

FERM

SH2

SH2

SH2

W

FERM

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

FN

FN

FN

FN

FN

FN

FN

MAM

FN

FN

FN

C2

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FN

FYVE

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

MEG2

SHP1

SHP2

CD45

PTP1B

TCPTP

PEST

LyPTP

Heavily

glycosylated

PTPm

PTPk

PTPr

PTPl

LAR

PTPs

PTPd

PTPa

PTPe

PTPg

PTPz

FERM

domain

PTP domain

Carbonic

anhydrase-like

Fibronectin III

Like repeat

Src Homology

domain 2

FN

Cadherin-like

DSP domain

Retinaldehyde

Binding protein-like

Merpin/A5/m

domain

MAM

FYVE-domain

FYVE

PEST-like

PEST

Lipid binding

domain

Immuno-

globulin-like

C2

PDZ domain

Tonks NK & Neel BG, Curr Opin Cell Biol. 2001, 13(2):182-95


Sequence alignment of amino acid residues at abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

phosphatase motif among human DSPs


Amino acid sequence homologies of human DSPs abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


Catalytic mechanism of DSPs abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


Mammalian MAP kinase cascades abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


MAPK and SAPK pathway in mammalian cells abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

T-x-Y at the activation loop


Function of map kinase phosphatases mkps
Function of MAP Kinase Phosphatases (MKPs) abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


Mechanism of action of MAP kinase phosphatases (MKPs) abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


Inactivation of MAP kinases (ERK) abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

by threonine or tyrosine dephosphorylation


The mammalian MAP kinase phosphatases (MPKs) abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal


PTPs and Cancer abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

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


PTPs and Cancer abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

PTEN Tumor Suppressor Mutated in various human cancers. Cowden disease

DEP1 Tumor suppressor Colon cancer susceptibility locus Scc1 (QTL in mice)

PTPkTumor 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


PTPs as Drug Targets abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

Immunosupression

Diabetes

& Obesity

Autoimmunity

& Allergy

PTPs

Infectious

diseases

Cancer

Epilepsy


S abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

(Inactive)

P

P

PTK

PTK

(Inactive)

(Active)

S

P

P

(Active)

Interactions Between PTKs and PTP– (1)

PTPs function as NEGATIVE Regulators

of Signal Transduction

Autophosphorylation

PTP

PTP


P abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

P

Interactions Between PTKs and PTPs—(2)

PTPs function as POSITIVE Regulators of

Signal Transduction

PTP

S

S

(Inactive)

(Active)

PTK


Important references abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

  • Hunter, T. (2000) Signaling-2000 and beyond. Cell, 100: 113-127

  • J. Schlessinger (2000) Cell signaling by receptor tyrosine kinases.

  • Cell, 103: 211-225

  • 3. Myers, M. et al. (2001) TYK2 and JAK2 are substrates of protein

  • tyrosine phosphatase 1B. J. Biol. Chem., 276: 47771-47774

  • Andersen, J. N. et al. (2001) Structural and evolutional relationships

  • among protein tyrosine phosphatase domains. Mol. Cell. Biol.,

  • 21: 7117-7136

  • 5. Tonks, N. K. (2003) PTP1B: From the sidelines to the front lines.

  • FEBS Letters, 546: 140-148


Additional references abnormality not found in any nonleukemic white blood cells, nor in any other cells of the patient's body. This abnormality is a reciprocal

  • 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 factor

  • receptor 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 dephosphorylation

  • of the activation segment of the insulin receptor by protein tyrosine

  • phosphatase 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.


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