What is Heparin-Binding Growth Factor Family?

Several extracellular heparin-binding proteins involved in regulation of growth and differentiation belong to a new family of growth factors. These growth factors are highly related proteins of about 140 amino acids that contain 10 conserved cysteines probably involved in disulphide bonds, and include pleiotrophin (also known as heparin-binding growth-associated molecule HB-GAM, heparin-binding growth factor 8 HBGF-8, heparin-binding neutrophic factor HBNF and osteoblast specific protein OSF-1).

Heparin-binding growth factor family is divided into 3 main classes including FGF-2, Midkine (MK) and Pleiotrophin (PTN).

-- FGF-2

Fibroblast growth factor-2 (FGF-2), a leading member of the FGF family of heparin-binding growth factors, contributes to normal as well as pathological angiogenesis. Pre-mRNA alternative splicing plays a key role in the regulation of cellular and tissular homeostasis and is highly controlled by splicing factors, including SRSFs. SRSFs belong to the SR protein family and are regulated by serine/threonine kinases such as SRPK1. FGF-2 promotes angiogenesis by activating a SRSF1/SRSF3/SRPK1 network that regulates VEGFR1 alternative splicing in endothelial cells, a process that could also contribute to lung tumor progression.

Fig 1 Graphical abstract for FGF-2-dependent regulation of sVEGFR1 splice variants

in endothelial cells and its contribution to angiogenesis and lung tumorigenesis

--Midkine (MK)

Midkine (MK) is one of the heparin-binding growth factors. Targeting the cytokine midkine (MK), which mediates NET formation in vitro, not only attenuates NET formation in vivo and the infiltration of polymorphonuclear neutrophils (PMNs) but also reduces fibrosis and preserves systolic function during EAM. Inhibition of NET formation in experimental autoimmune myocarditis (EAM) of mice substantially reduces inflammation in the acute phase of the disease. NETosis substantially contributes to the pathogenesis of myocarditis and drives cardiac inflammation, probably via MK, which promotes PMN trafficking and NETosis. Thus, MK as well as NETs may represent novel therapeutic targets for the treatment of cardiac inflammation.

Fig 2 The mechanism of action of MK

--Pleiotrophin (PTN)

Pleiotrophin (PTN) is associated with the development and metastasis of various tumors and it is a poor prognostic factor for the tumor patients. The high expression of PTN is significantly relevant to the advanced TNM stage and poor OS in tumor patients. Therefore, PTN can serve as a promising biomarker to predict unfavorable survival outcomes, and it may be a potential target for tumor treatment.

Heparin-binding growth factors, the major targets for drug discovery, provide a new research idea for drug intervention therapy of cardiac inflammation, cancers, etc.