Resolving HGF and HGFR: The Tystery of Hepatocyte Growth Factor and its Receptor

What is HGF?

Hepatocyte Growth Factor (HGF), also known as scatter factor, is a versatile cytokine initially identified for its potent stimulation of hepatocyte growth in primary cultures[1]. Later, it was recognized as a pivotal factor influencing cell motility in epithelial, muscle, and nerve cells[2]. HGF is synthesized and secreted as an inactive pro-HGF form (92 kDa) by stromal cells, including macrophages and fibroblasts. The conversion of pro-HGF to its active form involves cleavage between Arg494 and Val495, resulting in two covalently linked chains: a 62 kDa heavy chain and a 32-36 kDa light chain. Activation is facilitated by various proteases like urokinase, plasminogen activator, and HGF activator, with the latter being the most efficient, activated through thrombin cleavage of its precursor[3-5].

HGF functions as a ligand for the MET receptor tyrosine kinase[6-7]. The biologically active αβ heterodimeric HGF comprises a high-affinity MET-binding site in the α chain and a low-affinity site in the β chain[8-9]. Notably, only the active form of HGF can trigger MET-mediated biological responses.

The Versatile Roles of HGF in Cell Biology

HGF (Hepatocyte Growth Factor) serves as a pivotal growth factor with multifaceted functions in cell biology. Primarily, HGF stands as a crucial regulator of cell proliferation and migration. When tissue undergoes damage or stimulation, the neighboring cells release HGF, fostering the proliferation and migration of cells within the affected region[10], thereby facilitating tissue repair. Furthermore, HGF plays a pivotal role in the development of organs. During embryonic growth, HGF actively participates in the formation of various organs, including the lung, liver, and kidney.

Within the liver, HGF assumes a pivotal position in the process of liver regeneration. In instances of liver damage, the liberation of HGF prompts liver cell proliferation, aiding in the restoration of liver functionality post-injury. Additionally[11], HGF engages in diverse cellular signal transduction pathways by binding to its receptor, HGFR (MET). These pathways encompass a spectrum of factors including cell survival, proliferation, and migration, thereby exerting influence over cellular physiological and pathological processes.

However, HGF's excessive expression may also contribute to pathological conditions. In certain tumors, the abnormal release of HGF might accelerate the growth and migration of malignant cells, consequently fostering tumor development and metastasis[12]. Hence, HGF has emerged as a focal point in tumor biology research.

Fig.1 Structure and biologic function of HGF
Fig.1 Structure and biologic function of HGF

Deciphering the Molecular Structure of HGF

The intricate molecular architecture of Hepatocyte Growth Factor (HGF) revolves around two distinct polypeptide chains, referred to as the α-chain and β-chain. These chains are meticulously connected by disulfide bonds, culminating in the formation of a protein molecule marked by dual chains.

  1. Structure of the α Chain: Within HGF's makeup, the α-chain takes prominence with its array of domains. A noteworthy constituent among these is the Kringle domain, a realm containing a specific amino acid sequence that exerts a pivotal role in both the biological potency and the bonding with the HGF receptor (HGFR)[13]. This Kringle domain plays a pivotal role in steering HGF's signal transduction and functionality, facilitating interactions with the HGF receptor (also known as MET), thereby sparking intricate intracellular signaling pathways.
  2. Architecture of the β Chain: Complementing the α-chain is the β-chain, housing HGF's biologically active territory. The β-chain encompasses a tyrosine kinase domain, a protein segment recognized for its prowess in phosphorylating tyrosine residues[14]. This particular tyrosine kinase domain emerges as a linchpin in HGF's signal transduction. Its phosphorylation of specific tyrosine residues incites a cascade of intracellular signaling pathways, orchestrating processes like cell proliferation, migration, and survival, to name a few.
  3. Precursor and Active Configuration: HGF commences its journey secreted as an inactive precursor known as single-chain HGF. This initial form metamorphoses under the influence of specialized enzymes[15], cleaving the single-chain structure into the dynamic double-chain HGF. This transformative process liberates the biologically active segment housed within the β-chain. The cleavage procedure stands as a pivotal juncture, propelling HGF into a bioactive state, capable of forging connections with its receptor, HGFR, thus launching the intricate cellular signaling pathways.

In summation, HGF's intricate molecular composition underpins its diverse biological roles, spanning from cell proliferation and migration to the orchestration of signal transduction and tissue rejuvenation. The specific domains within the α-chain and β-chain, particularly the Kringle domain and the tyrosine kinase domain, emerge as pivotal players dictating HGF's biological activities and the elaborate course of signal transduction. By delving into the intricate interplay of structure and function within HGF, a deeper comprehension of its significance in the realms of cell biology and medical exploration emerges.

Expression of HGF and c-Met

HGF is expressed only by cells of mesenchymal origin[16]. However, c-Met is expressed mainly by epithelial cells. In addition, c-Met is expressed by various other cell types including vascular endothelial cells, lymphatic endothelial cells[17], neural cells[18], hepatocytes[19], hematopoietic cells[20], and pericytes. In many tumor cells, c-Met expression is activated by HGF through an autocrine loop. The activation or upregulation of both the ligand and the receptor in tumors is a negative prognostic indicator in human cancer.

Unraveling the HGF-HGFR Signaling Pathway: Insights and Implications

The HGF-HGFR signaling pathway constitutes a pivotal cellular communication mechanism encompassing the intricate interplay between hepatocyte growth factor (HGF) and its corresponding receptor, the hepatocyte growth factor receptor (HGFR, also known as MET). This signaling cascade stands as a critical orchestrator in the realm of cell biology and disease progression, governing an array of cellular functions and processes.

The journey of this signaling pathway commences with the binding of HGF to the HGFR receptor. HGF, a secreted protein, triggers receptor activation by binding to the extracellular domain of HGFR. This interaction induces a transformative shift within HGFR, propelling the activation of its intrinsic tyrosine kinase activity. This event catalyzes the tyrosine phosphorylation of HGFR itself, heralding the initiation of downstream signaling.

Activated HGFR sets into motion an intricate series of downstream signaling pathways, exerting influence on various cellular processes:

  1. MAPK Pathway: Activation of HGFR ignites the Ras protein, thereby unleashing the MAPK (mitogen-activated protein kinase) pathway. This intricate web of interactions governs cell proliferation, migration, and survival, acting as a linchpin in the intricate orchestration of cellular growth and propagation.
  2. PI3K-AKT Pathway: HGFR activation also triggers the activation of PI3K (phosphatidylinositol 3-kinase), subsequently culminating in the activation of AKT (protein kinase B). This pathway is instrumental in steering cell survival, proliferation, and anti-apoptotic competence, standing as a cornerstone in cellular physiological processes.
  3. STAT Pathway: Activated HGFR catalyzes the phosphorylation of STAT proteins (signal transducer and activator of transcription), ushering them into the nucleus where they partake in the intricate choreography of gene transcription. This pathway exercises influence over cell differentiation and growth.

The HGF-HGFR signaling pathway exerts its sway over diverse physiological and pathological processes. In the realm of normal physiology, it takes the helm in pivotal processes like organ development, tissue rejuvenation, and cellular proliferation. However, during pathological conditions, an aberrant HGF-HGFR signaling pathway may thrust cells into unbridled proliferation and migration, fueling the terrain for tumor development and metastasis. Delving into the regulatory nuances of the HGF-HGFR signaling pathway holds the key to comprehending disease progression and forging prospective therapeutic strategies. This intricate signaling avenue emerges as a potent target for drug development, holding the potential to pave novel avenues for tackling diseases, including cancer.

Fig.2 c-MET/HGF pathway[21]
Fig.2 c-MET/HGF pathway[21]

The Clinical Significance of HGF-HGFR

The HGF-HGFR signaling pathway holds paramount clinical importance, particularly in the domains of cancer therapy and tissue regeneration. The following elucidates its clinical significance:

  1. Cancer Treatment: The HGF-HGFR signaling pathway assumes a pivotal role in tumor growth, migration, and invasion, rendering it a prime target in cancer therapy. In numerous tumor types, the aberrant activation of HGF and HGFR spurs unchecked proliferation and migration of malignant cells, fueling tumor development and metastasis. Therapeutic inhibitors designed to target this signaling pathway can curtail HGF-HGFR activity, effectively impeding tumor cell proliferation and migration. Several drugs tailored for treating diverse cancers, such as non-small cell lung cancer and colorectal cancer, have emerged as a result.
  2. Precision Targeting: With the HGF-HGFR pathway exhibiting heightened activity across various tumor types, drugs designed to counteract this pathway fall under the category of targeted therapy. These drugs can selectively interfere with pathway activity, minimizing repercussions on normal cells. This targeted therapeutic approach holds promise for delivering more potent treatments, mitigating treatment-associated side effects, and enhancing overall patient survival.
  3. Reversing Drug Resistance: Certain tumors develop resistance to treatment, diminishing the effectiveness of drugs. Research has demonstrated a link between the HGF-HGFR pathway and drug resistance development. By inhibiting this pathway, drug resistance can be reversed, rekindling tumor cell responsiveness to treatment and thereby extending patient survival.
  4. Tissue Restoration and Regeneration: The HGF-HGFR signaling pathway also wields significance in tissue repair and regeneration. Following trauma or injury, the release of HGF aids in repairing damaged tissue, restoring functionality through the stimulation of cell proliferation and migration. This bears potential implications for applications like tissue transplantation, organ injury treatment, and tissue engineering endeavors.

To conclude, the HGF-HGFR signaling pathway boasts extensive clinical relevance. Serving as a focal point in cancer therapy, it furnishes a precise avenue to curtail tumor cell proliferation and migration, promising enhanced therapeutic outcomes.

HGF and HGFR Protein

Recombinant Human HGF Protein

Click here for more HGF

Synonym:Scatter Factor (SF), Hepatopoietin (HPTA), HGF, HGFB, F-TCF.

Recombinant Human c-MET Protein (His & Fc Tag)

Click here for more c-MET

Synonym:AUTS9 c met D249 Hepatocyte growth factor receptor HGF HGF receptor HGF/SF receptor HGFR MET Met proto oncogene Met proto oncogene tyrosine kinase MET proto oncogene, receptor tyrosine kinase Met proto-oncogene Met proto-oncogene (hepatocyte growth factor receptor) Met protooncogene MET_HUMAN Oncogene MET Par4 Proto-oncogene c-Met RCCP2 Scatter factor receptor SF receptor Tyrosine-protein kinase Met

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