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ALK1 signaling in development and disease: new paradigms

Abstract

Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.

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Abbreviations

ActRII:

Activin receptor type II

ACVRL1:

Activin A receptor like type I (gene)

ALK1:

Activin A receptor like type I (protein)

AMHRII:

Anti-mullerian hormone receptor type 2

ANGPT2:

Angiopoietin 2

AV:

Arterial/venous

AVM:

Arteriovenous malformation

BMP:

Bone morphogenetic protein

BMPR:

Bone morphogenetic protein receptor (BMPR)

CX40:

Connexin 40 (also known as GJA5)

CXCR4:

C-X-C motif chemokine receptor type 4

CXCL12:

C-X-C motif chemokine ligand type 12

DLL4:

Delta-like 4

E:

Embryonic day

EC:

Endothelial cell

EC50:

Effective concentration-50

EDN1:

Endothelin 1

EFNB2:

Ephrin B2

ENG:

Endoglin

ESM1:

Endothelial cell specific molecule 1

GDF:

Growth and differentiation factor

GS:

Glycine and serine rich

HEY:

Hes-related family bHLH transcription factor with YRPW motif

HHT:

Hereditary hemorrhagic telangiectasia

ID:

Inhibitor of differentiation

JAG1:

Jagged 1

KD:

Kinase domain

KLF2:

Krüppel-like factor 2

LDL:

Low-density lipoprotein

MH1:

Mad homology 1

miRNA:

MicroRNA

MIS:

Müllerian-inhibiting substance

mTORC1:

Mechanistic target of rapamycin complex 1

NICD:

Notch intracellular domain

NR2F2:

Nuclear receptor subfamily 2 group F member 2

PAH:

Pulmonary arterial hypertension

PDGF:

Platelet-derived growth factor

PI3K:

Phosphatidylinositol-3-kinase

PVH:

Pulmonary venous hypertension

RBPJ:

Recombination signal binding protein for immunoglobulin kappa J region

RTK:

Receptor tyrosine kinase

TGFβ:

Transforming growth factor beta

TβRII:

Transforming growth factor beta receptor 2

TMEM100:

Transmembrane protein 100

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

YAP1:

Yes-associated protein-1

ZP:

Zona pellucida

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Acknowledgements

BLR is supported by NIH R01HL133009, NIH R01HL136566, and by the University of Pittsburgh Vascular Medicine Institute, the Hemophilia Center of Western Pennsylvania, and the Institute for Transfusion Medicine. APH is supported by NIH R01GM58670 and P30CA054174.

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Roman, B.L., Hinck, A.P. ALK1 signaling in development and disease: new paradigms. Cell. Mol. Life Sci. 74, 4539–4560 (2017). https://doi.org/10.1007/s00018-017-2636-4

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Keywords

  • Activin A receptor like type 1
  • Hereditary hemorrhagic telangiectasia
  • Angiogenesis
  • Arteriovenous malformation
  • Bone morphogenetic protein
  • Endoglin