HBEGF

What is HBEGF protein?

HBEGF (heparin binding EGF like growth factor) gene is a protein coding gene which situated on the long arm of chromosome 5 at locus 5q31. Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene. HB-EGF-like growth factor is synthesized as a membrane-anchored mitogenic and chemotactic glycoprotein. An epidermal growth factor produced by monocytes and macrophages, due to an affinity for heparin is termed HB-EGF. It has been shown to play a role in wound healing, cardiac hypertrophy and heart development and function. The HBEGF protein is consisted of 208 amino acids and its molecular mass is approximately 23.1 kDa.

What is the function of HBEGF protein?

HBEGF can promote the proliferation and differentiation of multiple cell types by activating members of the epidermal growth factor receptor (EGFR/ErbB) family. After wound healing and tissue injury, the expression of HBEGF is up-regulated, which promotes cell migration and neovascularization. HBEGF is also involved in inflammatory responses, influencing inflammatory processes and the progression of related diseases by regulating the function of immune cells and the production of inflammatory mediators.

HBEGF Related Signaling Pathway

EGFR/ErbB family signaling pathway: HBEGF, a member of the epidermal growth factor family, activates downstream signaling pathways such as Ras-Raf-MEK-ERK and PI3K-Akt by binding to EGFR (epidermal growth factor receptor) or other ErbB family receptors on the cell surface.

Cell cycle regulation: By activating downstream effectors such as ERK and Akt, HBEGF can influence cell cycle progression and promote the transition of cells from G1 phase to S phase, thus promoting cell proliferation.

Angiogenesis: HBEGF can stimulate the proliferation and migration of endothelial cells and promote the formation of new blood vessels, which is achieved by activating angiogenesis related factors such as VEGF (vascular endothelial growth factor).

HBEGF Related Diseases

The expression of HBEGF is abnormally increased in many cancers, such as breast cancer, colorectal cancer and gastric cancer, and promotes the growth, differentiation and metastasis of tumor cells by activating the ErbB receptor family. In cardiovascular diseases such as atherosclerosis and hypertension, the increased expression of HBEGF may be related to the proliferation of vascular smooth muscle cells and the formation of new blood vessels. It is also associated with chronic inflammatory diseases and metabolic diseases.

Fig1. The working hypothesis of HB-EGF in metabolic disease development. (Seonwook Kim, 2020)

Bioapplications of HBEGF

In the field of skin science and beauty, HBEGF is added to skin care products for anti-aging and improved skin appearance due to its properties of promoting collagen synthesis and improving skin texture. Using HBEGF's ability to bind to specific cell surface receptors, it can be used as part of a drug delivery system to improve drug targeting and therapeutic efficacy.

Case Study 1: Tianwen Lai, 2018

Although airway fibrosis and epithelial-mesenchymal transition (EMT) contribute to airway remodeling in chronic obstructive pulmonary disease (COPD), the mechanisms underlying their development have not been fully elucidated. In the present study, the researchers aimed to assess heparin-binding epidermal growth factor (HB-EGF) expression in the airways of patients with COPD and to elucidate the possible role of HB-EGF in the pathology of COPD.

The relationships between HB-EGF expression, disease severity, collagen deposition (fibrosis), and EMT were investigated. In vitro, human bronchial epithelial (HBE) cells and lung fibroblast cells exposed to the recombinant HB-EGF, collagen deposition and EMT were assessed. They found that sputum HB-EGF expression was significantly increased in patients with COPD compared with non-smokers and smokers without COPD. There was a significant positive correlation between sputum HB-EGF and COPD assessment test (CAT) score. In vitro, HB-EGF promoted collagen production in lung fibroblasts. Moreover, HB-EGF induced the EMT process through induction of N-and E-cadherin, and vimentin expression in HBE cells.

Fig1. Collagen I expression upon stimulation by HB-EGF as determined by western blot analysis.

Fig2. Recombinant human HB-EGF protein activated ERK and p38 phosphorylaton in a dose-dependent manner.

Case Study 2: Angela L Gaviglio, 2017

High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here the researchers identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma. HBEGF mRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high-stage disease containing very little stroma or HBEGF expression. In 3 human neuroblastoma cell lines (SK-N-AS, SK-N-BE2, and SH-SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF-induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up-regulation of the inhibitor of DNA binding transcription factor.

Fig3. Western blot for differentiation markers after 72 h of HBEGF treatment in BE2 and SK-N-AS.

Fig4. Western blots for differentiation markers after 72-h treatment with 10 ng/ml soluble (s)TβRIII or sCD44 or 100 ng/ml sGPC1, sGPC3, or sSDC3 in the absence or presence of 0.5 ng/ml HBEGF in 5Y cells.

HBEGF has several biochemical functions, for example, epidermal growth factor receptor binding,growth factor activity,heparin binding. Some of the functions are cooperated with other proteins, some of the functions could acted by HBEGF itself. We selected most functions HBEGF had, and list some proteins which have the same functions with HBEGF. You can find most of the proteins on our site.

HBEGF has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with HBEGF here. Most of them are supplied by our site. Hope this information will be useful for your research of HBEGF.

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