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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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slide1

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]

slide2

Phosphorylation is reversible

PTPs

P

P

P

P

Y

Y

Y

Y

Protein

Protein

Y

Y

P

P

PTKs

slide3

Protein modules in

the control of intracellular

signaling pathways

Docking proteins function

as platforms for the recruitment

of signaling molecules

slide4

Models for activation of

Signaling proteins

A). By membrane translocation

B). By conformational change

C). By tyrosine phosphorylation

slide5

Signaling pathways

activated by receptor

tyrosine kinases

Mechanisms for attenuation

of receptor tyrosine kinases

slide8

Activation of receptor tyrosine kinases

Juxtamembrane

region

N-terminal

kinase lobe

Substrate precluding

loop

Substrate accessible

loop

C-terminal tail

slide9

Activation of c-Src

  • Two modes of intrinsic inhibition
  • by interactions between:
  • SH2 domain and
  • phosphorylated Y527;
  • (2) SH3 domain and
  • Polyproline region.
slide10

Activation of PKB/Akt

PH domain precludes

Kinase access by PDK-1

slide11

*

*

slide12

*

*

slide14

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

slide15

W

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

slide16

Classification of Protein Tyrosine Phosphatases

Non-transmembrane PTPs

Receptor-like PTPs

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

slide17

C-terminal

- 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

slide21

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)

http://ptp.cshl.edu

slide22

Conserved fold of PTP domains

N-terminal

Central a3-helix

Andersen et al Mol. Cell. Biol. 2001

slide25

W

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

slide27

Sequence alignment of amino acid residues at

phosphatase motif among human DSPs

slide31

MAPK and SAPK pathway in mammalian cells

T-x-Y at the activation loop

slide35

Inactivation of MAP kinases (ERK)

by threonine or tyrosine dephosphorylation

slide37

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

slide38

PTPs and Cancer

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

slide39

PTPs as Drug Targets

Immunosupression

Diabetes

& Obesity

Autoimmunity

& Allergy

PTPs

Infectious

diseases

Cancer

Epilepsy

slide40

S

(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

slide41

P

P

Interactions Between PTKs and PTPs—(2)

PTPs function as POSITIVE Regulators of

Signal Transduction

PTP

S

S

(Inactive)

(Active)

PTK

slide42

Important references

  • 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
slide43

Additional references

  • 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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