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Tie receptors: new modulators of angiogenic and lymphangiogenic responses

Abstract

Angiogenesis is required for normal embryonic vascular development and aberrant angiogenesis contributes to several diseases, including cancer, diabetes and tissue ischaemia. What are the molecular mechanisms that regulate this important process? The Tie family of receptors and their ligands, the angiopoietins, are beginning to provide insight into how vessels make decisions such as whether to grow or regress — processes that are important not only during development but throughout an organism's life.

Key Points

  • Endothelial-cell-specific receptor tyrosine kinases can be subgrouped into the Tie and vascular endothelial growth factor (VEGF) receptor families. The Tie receptor family has two members, Tie1 and Tie2.

  • Tie receptors are required for the angiogenic remodelling of vessels during embryonic development and for vessel stabilization in quiescent adult vasculature.

  • Tie receptors also contribute to the abnormal vascular growth that is associated with many pathological conditions such as venous malformations, tumour growth and rheumatoid arthritis.

  • Signal-transduction pathways controlled by the Tie receptors are overlapping but independent as Tie1 and Tie2 do not seem to functionally compensate for one another.

  • Angiopoietins, the ligands for the Tie2 receptor, might have either agonistic (Ang1 and Ang4) or antagonistic (Ang3) actions regulating vascular expansion and survival. Ang2 can stimulate or inhibit angiogenesis in different contexts. In addition, it seems to be important for the development of lymphatic vessels.

  • Ang1 facilitates phosphatidylinositol-3-OH kinase (PI(3)K)-dependent endothelial cell survival through stimulation of the serine–threonine kinase Akt, leading to protection from apoptosis.

  • Ang1 also stimulates endothelial cell migration, sprouting and tubule formation. Endothelial cell motility induced by Tie2 activation seems to be regulated through activation of the PI(3)K, the adaptor protein Nck and focal adhesion kinase.

  • Three tyrosine phosphatases participating in the regulation of Tie2 receptor signalling have been characterized.

  • Tie1 signal transduction has been difficult to study as no ligand for this receptor has been identified. However, recent studies indicate that Tie1 participates in ligand-independent signalling. Tie1 might also form heterodimers with Tie2 and therefore modulate Tie2 signalling.

  • Increasing our knowledge of Tie receptor signalling pathways might lead to the development of more effective and refined targets for angiogenic therapies.

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Figure 1: Blood and lymph vascular systems.
Figure 2: Structure of endothelial-cell receptor tyrosine kinases and growth factors involved in vasculogenesis, angiogenesis and lymphangiogenesis.
Figure 3: The angiopoietins.
Figure 4: Venous malformation associated with a TIE2 mutation.
Figure 5: Regulatory elements of Tie1 and Tie2 genes.
Figure 6: Tie2 signal transduction, showing the known binding partners for Tie2.

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Acknowledgements

We thank G. Yancopoulos, C. Kontos, M. Detmar and Z. Master for discussions of unpublished data. The authors also acknowledge the support of the Canadian Institutes of Health Research (the former Medical Research Council (MRC) of Canada), the National Cancer Institute of Canada, the Juvenile Diabetes Foundation International and Cancer Care Ontario to D.J.D. D.J.D. is a scientist of the MRC of Canada. N.J. was supported by an MRC studentship award. K.I. and K.A. are supported by the Finnish Academy, the Sigrid Juselieus Foundation, the University of Helsinki Hospital, the State Technology Development Center as well as by EU Biomed programme. We apologize for the failure to cite many important contributions to this field owing to space limitations.

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DATABASE LINKS

VEGF

VEGFR-1

VEGFR-2

VEGFR-3

neuropilin-1

VEGF-C

VEGF-D

angiopoietins

Tie2

Tie1

Ang1

Ang4

Ang2

Ang3

HIF-2

Grb2

MAPK

Akt

Bad

caspase-9

nitric oxide synthase

survivin

BIR-1

FAK

MMP-2

Dok-R

Pak

Grb7

Shp2

protein kinase C

ANG2443

aANG2B

mAng3

cadherins

selectins

integrins

VE-cadherin

α-catenin

β-catenin

γ-catenin

vinculin

α-actinin

Sos

CAS

paxillin

HIF-1α

HIF-1β

HIF-2α

p53

Mdm2

Glossary

MESODERM

Third germ layer in the embryo, formed during the process of gastrulation.

PRIMARY CAPILLARY PLEXUS

Simplified, honeycomb-like network of rudimentary blood vessels that is especially evident in the yolk sac vasculature.

PERIENDOTHELIAL SUPPORT CELLS

Mesenchymal cells that surround the endothelial component of mature blood vessels. They include pericytes and vascular smooth muscle cells.

PERICYTES

Support cells of capillaries (referred to as smooth muscle cells in larger vessels).

LYMPHANGIOGENESIS

Development and growth of lymphatic vessels.

STROMA

Connective tissue made up of cells, such as fibroblasts, and matrix, such as collagen.

LYMPHOEDEMA

Disease caused by obstruction or defects of the lymphatic vessels, resulting in accumulation of interstitial tissue fluid.

ENDOCARDIUM

Endothelial lining of the cardiac lumen.

SRC

Cytoplasmic tyrosine kinase first identified as a transforming oncogene in an avian retrovirus. This kinase is the prototypic kinase from which src-homology regions were first described.

ANOIKIS

Induction of programmed cell death by detachment of cells from the extracellular matrix.

FIBRIN MATRICES

Cell-culture substratum used in in vitro assays of angiogenesis to examine endothelial cell differentiation. Based on the premise that endothelial cells invade blood clots during wound repair and that fibrin is the major component of a blood clot.

OEDEMA

Accumulation of tissue fluid leading to swelling.

STATS

Family of cytoplasmic transcription factors (signal transducers and activators of transcription) that dimerize upon phosphorylation and translocate to the nucleus to activate transcription of target genes.

GLIOBLASTOMA

Malignant brain tumour, predominantly located in the cerebral hemispheres.

KAPOSI'S SARCOMA

Angiogenic tumour composed of endothelial and spindle cells (elongated fibroblast-like shaped cells that usually express endothelial markers).

ETS

Group of winged helix–loop–helix transcription factors that contain an ETS DNA-binding domain.

CHORIOALLANTOIC MEMBRANE

An extremely vascular envelope created by fusion of the allantoic membrane with the chorion. Functions in the exchange of wastes and metabolites in the embryo.

NCK

SH2/SH3-domain-containing adaptor molecule that has been implicated in cell migration through transduction of signals to the actin cytoskeleton.

SHP2

SH2-domain-containing cytoplasmic tyrosine phosphatase.

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Jones, N., Iljin, K., Dumont, D. et al. Tie receptors: new modulators of angiogenic and lymphangiogenic responses. Nat Rev Mol Cell Biol 2, 257–267 (2001). https://doi.org/10.1038/35067005

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