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Sprouty proteins, masterminds of receptor tyrosine kinase signaling

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Abstract

Angiogenesis relies on endothelial cells properly processing signals from growth factors provided in both an autocrine and a paracrine manner. These mitogens bind to their cognate receptor tyrosine kinases (RTKs) on the cell surface, thereby activating a myriad of complex intracellular signaling pathways whose outputs include cell growth, migration, and morphogenesis. Understanding how these cascades are precisely controlled will provide insight into physiological and pathological angiogenesis. The Sprouty (Spry) family of proteins is a highly conserved group of negative feedback loop modulators of growth factor-mediated mitogen-activated protein kinase (MAPK) activation originally described in Drosophila. There are four mammalian orthologs (Spry1-4) whose modulation of RTK-induced signaling pathways is growth factor- and cell context-dependant. Endothelial cells are a group of highly differentiated cell types necessary for defining the mammalian vasculature. These cells respond to a plethora of growth factors and express all four Spry isoforms, thus highlighting the complexity that is required to form and maintain vessels in mammals. This review describes Spry functions in the context of endothelial biology and angiogenesis, and provides an update on Spry-interacting proteins and Spry mechanisms of action.

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Abbreviations

Ang:

Angiopoietin

c-Cbl:

Cellular homologue of Casitas B-lineage lymphoma proto-oncogene product

EGF:

Epidermal growth factor

EGFR:

EGF receptor

eNOS:

Endothelial nitric oxide synthase

ERK:

Extracellular signal-regulated kinase

FGF:

Fibroblast growth factor

FGFR:

FGF receptor

GDNF:

Glial-derived neurotrophic factor

Grb2:

Growth factor receptor-bound protein 2

HMVEC:

Human microvascular endothelial cell

Hrs:

Hepatocyte growth factor-regulated tyrosine kinase substrate

HUVEC:

Human umbilical vein endothelial cell

MAPK:

Mitogen-activated protein kinase

MEK:

MAPK and ERK kinase

Mnk1:

Mitogen-activated protein kinase-interacting kinase 1

PDGF:

Platelet-derived growth factor

PKC:

Protein kinase C

PLC:

Phospholipase C

PP2A:

Protein phosphatase 2A

RBD:

Raf1-binding domain

RTK:

Receptor tyrosine kinase

Shp2:

SH2-domain-containing protein tyrosine phosphatase 2

SIAH2:

Seven-in-Absentia Homolog 2

SMC:

Smooth muscle cell

Sos1:

Son of Sevenless 1

Spry:

Sprouty

Spred:

Spry-related proteins with Enabled/vasodilator-stimulated phosphoprotein homology 1 domain

SPR:

Spry-related domain

VEGF:

Vascular endothelial growth factor

VEGFR:

VEGF receptor

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Acknowledgments

The authors are grateful to Drs. Imke Albrecht, Anna Fantozzi, and Tibor Schomber for critically reading the manuscript. We apologize to all colleagues whose important work we could not cite due to space limitations. M.A.C. was initially supported by a post-doctoral fellowship from the International Agency for Research on Cancer (IARC–WHO). Research in the laboratory of the authors is supported by the Swiss National Science Foundation, Swiss Bridge Award, Krebsliga Beider Basel, Swiss Cancer League, EU-FP6 Framework programmes LYMPHANGIOGENOMICS LSHG-CT-2004-503573 and BRECOSM LSHC-CT-2004-503224, SNF-NCCR Moleculary Oncology, and Novartis Pharma Inc.

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Cabrita, M.A., Christofori, G. Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis 11, 53–62 (2008). https://doi.org/10.1007/s10456-008-9089-1

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