June 20, 2021

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2nd Part: Growth factors and receptor tyrosine kinases (RTKs)

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2nd Part: Growth factors and receptor tyrosine kinases (RTKs)

2nd Part: Growth factors and receptor tyrosine kinases (RTKs).   In the first part, we talked about the classification, structure and function of RTKs, and took an important family, epidermal growth factor receptor (EGFR) family RTK as an example, to explain the binding mode of ligand and receptor (Learning the pathway first phase) . In 2nd part, we give an overview of RTKs from other families.

1st Part:  Growth factors and receptor tyrosine kinases (RTKs)

01 Platelet-derived growth factor (PDGF) receptors and related receptor families

2nd Part: Growth factors and receptor tyrosine kinases (RTKs)

The figure above is a schematic diagram of the platelet-derived growth factor (PDGF) receptor family ligands and receptor activation modes. Currently, there are four main ligands identified to activate PDGFR: PDGFA, PDGFB, PDGFC and PDGFD. They form active homodimers (AA, BB, CC, DD) and heterodimers (AB) through disulfide bonds. When the dimer ligand binds to the receptor, it causes the dimerization (αα, ββ, αβ) of different subtypes of the receptor (PDGFR-α, PDGFR-β), and further transmits the signal to the cell, causing intracellular The effect is produced.

Studies have found that PDGF is closely related to the tumorigenesis and growth process, especially it can promote tumor angiogenesis. The PDGFR pathway is closely related to another signal pathway related to tumor angiogenesis—VEGFR pathway. Most drugs involving PDGFR are dual-target or multi-target, such as Sunitinib, Axitinib, Cediranib.

In addition, in addition to the aforementioned PDGF receptors (PDGFR-α, PDGFR-β), this family also includes receptors for SCF, Flt-3LG and M-CSF/IL-34 (see Table 1 in the previous issue).


  • SCF: Stem Cell Factor, also known as: KITLG (ie: KIT ligand); receptor: KIT/SCFR;
  • FLT3LG: FMSlike tyrosine kinase-3 ligand; the receptor is FLT3;
  • MCSF: Macrophage colony stimulating factor (MCSF) and interleukin-34 (IL34) receptors are both CSF1R;

02 Vascular endothelial growth factor (VEGF) receptor family

Intravascular epidermal growth factor (VEGF) is mainly composed of five members: VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor PGF/PIGF (VEGF E and VEGF F are the source of snake venom, which is not used here). Discuss). The intravascular epidermal growth factor receptor (VEGFR) includes three types: VEGFR1, VEGFR2 and VEGFR3.

2nd Part: Growth factors and receptor tyrosine kinases (RTKs)

The main mode of action of VEGF and VEGFR is shown in the figure above. Among them, VEGFR-2 is mainly expressed in vascular endothelial cells and is the main receptor of VEGF. VEGFA/VEGFR-2 is the most important pathway for inducing angiogenesis. Because tumor cells grow and metabolize vigorously, they need to supply energy through new blood vessels, so targeting the VEGF/VEGFR pathway is an idea to inhibit tumor growth.

As we mentioned earlier, there are crossovers between many RTKs pathways, and VEGFR is no exception. The current FDA-approved drugs involving VEGFR targets are multi-target drugs: midostaurin (acute myeloid leukemia, mast cell leukemia), lenvatinib (differentiated thyroid cancer), nintedanib (idiopathic pulmonary fibrosis), axitinib (renal cell carcinoma), regorafenib (colorectal cancer, lung cell carcinoma, gastrointestinal stromal tumor), cabozantinib (renal cell carcinoma, lung cell carcinoma, medullary thyroid carcinoma), ponatinib (chronic myeloid leukemia, acute lymphoid Cellular leukemia), vandetanib (thyroid cancer), pazopanib (renal cell carcinoma, soft tissue sarcoma), sunitinib (renal cell carcinoma, gastrointestinal stromal tumor, pancreatic neuroendocrine tumor) and sorafenib (thyroid cancer, renal cell carcinoma).

Monoclonal antibodies against VEGF have also been approved for marketing. For example, Bevacizumab can bind to VEGF with high affinity and specificity and inhibit tumor vascular proliferation. It has been approved for marketing for the treatment of metastatic colon cancer.

03 Insulin receptor (INSR) family

2nd Part: Growth factors and receptor tyrosine kinases (RTKs)

The insulin receptor family includes insulin receptor (INSR), insulin-like growth factor receptor (IGFR), and insulin receptor-related receptor (INSRR). Insulin receptor family members can combine with their respective ligands: insulin (Insulin, INS), insulin-like growth factor (IGF-1 or IGF-2) to play a kinase role.

The diagram of the mode of action between the ligands INS, IGF1, IGF2 and different receptors is shown in the figure above. According to tissue specificity, insulin receptor (INSR) has two subtypes, A and B. IGF-2 and INS can bind to INSR-A receptors expressed in many epithelial tissues (induce homodimerization or interact with INSR-B). Heterodimerization) to promote cell growth; while INSR-B is a highly specific insulin receptor, which is mainly expressed in INS sensitive tissues. Only INS can induce the production of INSR-B homodimers and regulate Glucose homeostasis. In addition, IGF1 and IGF2 can induce the homodimerization of IGF1R, as well as the heterodimerization of INSR (A or B) and IGF1R.

At this point, some readers must ask: Is there IGF2R? In fact, there are, but after IGF2R is combined with IGF2, it cannot transcribe the signal, but causes pathway inhibition, so we won’t mention it here. Studies have shown that INSR-A and IGF1R are highly expressed in tumor cells; the PI3K pathway (introduced in the fourth phase) is the main pathway downstream of INS and IGF activating the corresponding receptors. On the contrary, IGF2R shows tumor suppressor function.

04  Fibroblast growth factor (FGF) and its receptor

2nd Part: Growth factors and receptor tyrosine kinases (RTKs)

There are 18 kinds of cytokines in the fibroblast factor family, and the corresponding ones are 4 kinds of fibroblast receptors (FGR1, FGR2, FGR3, FGR4). The main function of FGF-FGFR is to amplify the signal cascade of FGF signal transduction to RAS-ERK and PI3K-AKT.

FGR1, FGR2 and FGR3 all have two subtypes b and c, which are expressed in mesenchymal (conjunctival) tissues or epithelial tissues. The simple action mode diagram is shown in the figure above, and only 7 types of FGF are shown in the figure.

The abnormal function of FGFR is found in a variety of tumors, among which gene amplification, gene mutation and chromosome rearrangement are the main reasons for the abnormal activation of FGFR. At present, there are few single inhibitors against FGFR, and most of them are multi-target inhibitors.

05 Hepatocyte growth factor (HGF) and c-MET receptor

Hepatocyte growth factor (HGF) mainly plays a biological role through the specific receptor c-MET on the cell membrane. c-MET is a transmembrane receptor with autonomous phosphorylation activity encoded by the proto-oncogene c-MET. It is a heterodimer composed of 50 KD α subunit and 145 KD β subunit. HGF has two c-MET receptor binding domains, and its precursor is hydrolyzed by proteolytic enzymes to produce an active form. The mature HGF molecule consists of an alpha chain with a molecular weight of 96KD and a beta chain with a molecular weight of 34KD.

HGF is secreted by mesenchymal cells, but c-MET receptors are mainly expressed in epithelial cells, so HGF is considered to be a mediator of epithelial-mesenchymal interaction. A typical sign of cell canceration is the appearance of epithelial-mesenchymal transition, and c-MET is believed to play a key driving role in it.

Studies have found that c-MET is abnormally expressed in a variety of tumors due to c-MET gene amplification, mutation, chromosome rearrangement, etc., and inappropriate activation of c-MET promotes cell proliferation, cell motility, invasiveness and angiogenesis. And it is associated with a more aggressive phenotype and a lower survival rate.

06  Glial cell neurotrophic factor (GDNF) and RET receptor

The glial cell neurotrophic factor (GDNF) family includes four members: neurturin, persephin, artemin and GDNF. GDNF can be specifically bound by the extracellular protein GFRα1/2/3/4, but because GFRα1/2/3/4 lacks transmembrane and intracellular domains, it cannot complete signal transduction alone.

Therefore, GFRα activates downstream pathways by promoting the phosphorylation of the RET protein receptor and making RET enter an activated state. RET is a receptor tyrosine kinase encoded by the c-RET proto-oncogene. Phosphorylated RET activates its downstream mitogen-activated protein kinases MAPK, P13 kinase, etc., leading to the activation of a series of intracellular pathways, thereby Play the physiological functions of GDNF family neurotrophic factors.

Mutations in RET are associated with type II multiple endocrine tumors. Mutations in the RET gene can be observed in medullary thyroid carcinoma (MTC), and the mutation forms are mainly point mutations. In general, RET gene mutations are relatively low frequency, and the main form of mutation is fusion with other genes.

07 Anaplastic lymphoma kinase receptor (ALK) and leukocyte receptor tyrosine kinase receptor (LTK)

ALK (anaplastic lymphoma kinase) and LTK (leukocyte receptor tyrosine kinase) were first discovered in lymphoma. In most normal cells, ALK is in an inactive state. When the ALK gene is mutated, it often leads to abnormal activation of the protein. ALK activating mutations mainly occur in neuroblastoma, and ALK activating mutations can also be detected in tumors such as thyroid cancer and lung cancer.

As no ligand for ALK has been identified, ALK has been an orphan receptor for a long time (researchers have identified Pleiotrophin (PTN) and Midkine (MK) that can bind to ALK, but there is a lot of controversy). In January 2015, the research team of Joseph Schlessinger, director of the Department of Pharmacology of Yale University School of Medicine, published a paper in Science that herparin (heparin) is the true receptor of ALK.

The ALK small molecule inhibitors currently on the market include the first-generation crizotinib (Crizotinib); the second-generation ceritinib (Ceritinib), alectinib (Alectinib), and brigatinib (Brigatinib); and 3 Generation of Lorlatinib (Lorlatinib). The domestically produced second-generation drug Ensartinib was also launched last year.

08 Angiopoietin (ANG) and TIE receptors

Angiogenesis is regulated by many complementary and complex signal pathways existing in the human body. The three main pathways are: vascular endothelial growth factor (VEGF)-vascular endothelial growth factor receptor (VEGFR), angiopoietin (ANG)-TIE2 axis and DLL4-Notch pathway.

The ANG family is the only pro-angiogenic factor that contains both agonistic and inhibitory effects. It contains three members of ANG1, 2 and 4, and participates in the homodimerization of the tyrosine kinase receptor TIE-2 on endothelial cells. Angiogenesis; At the same time, ANG-2 can also inhibit angiogenesis by inducing heterodimerization of TIE-1 and TIE-2.

09  Ephrins and EPH receptor

Erythropoietin produces hepatocyte receptor (Eph) and its ligand ephrins, as the largest subgroup of the tyrosine protein kinase receptor family, and plays a key role in cell adhesion, localization, migration and differentiation.

Ephrins can be divided into two types, A and B, corresponding to two types of EPH receptors, and their interaction mode has not yet been fully studied. EPH receptor-mediated intramolecular signal transmission is mainly mediated by intracellular tyrosine kinase ABL and guanylate exchange factor of Rho GTPase, which activate or inhibit cell proliferation/migration.

10  Neurotrophic tyrosine kinase receptor (NTRK) / tropomyosin receptor kinase (TRK)

Tropomyosin receptor kinase (TRK), also known as Neurotrophin receptor kinase (NTRK), is a family of receptor tyrosine kinases, including NTRK1, The three receptors TrkA, TrkB and TrkC encoded by NTRK 2 and NTRK3 genes. In healthy tissues, pathways composed of ligands such as NTRK and nerve growth factor (NGF) participate in the development and function of the nervous system and cell survival, and play an important role in healthy tissues.

In some cases, the NTRK gene is fused with an unrelated gene, resulting in uncontrolled activation of the Trk signal, which can lead to cancer. In common cancers such as lung cancer, breast cancer, and colorectal cancer, only 1% to 5% of patients have NTRK gene fusion, while some rare cancers, such as infantile fibrosarcoma and secretory breast cancer, have NTRK fusion frequency. Up to 90%~100%. Drugs marketed for NTRK fusion mutations and drugs under research have significant clinical effects, so NTRK is also called a “diamond” gene.

At present, there are two drugs marketed globally for the treatment of NTRK fusion gene solid tumors, namely Bayer/LOXO’s larotinib (approved by the FDA in November 2018) and Roche’s entritinib (2019 August Approved by the FDA in September).

11  TAM receptor

The TAM receptor includes three members, namely: TYRO3, AXL and MERTK receptors. Corresponding to it are two ligands: GAS6 and PROS1. The gene of this receptor family was originally cloned from leukemia cells and is considered to be a proto-oncogene. Its expression level is related to the malignancy of solid tumors, especially glioblastoma, but no gene mutations or rearrangements have been found. .

12 Discoid domain receptor (DDR receptor)

Discoidindomain receptors-DDRs are receptor-type protein tyrosine kinases, including DDR1 and DDR2. The extracellular domain of this type of protein contains a structure similar to Dictyostelium discoideum lectin discoid domain 1. It is called the discoid domain (DR zone); secondly, there is a long near membrane zone (JM zone) between the DR zone and the transmembrane zone.

DDRs are widely expressed in human and mouse tissues, and can specifically bind to and be activated by a variety of collagens, and participate in a variety of disease processes, such as the occurrence and development of tumors, inflammatory reactions, and fibrosis.

13 Receptor Tyrosine Kinase-like Orphan Receptor (ROR)

The receptor tyrosine kinase-like orphan receptor (ROR) family includes two receptors, ROR1 and ROR2. Unlike the ROR family in nuclear receptors, ROR is a type of membrane receptor, because the ligand for the ROR protein was unknown when it was first discovered. , So it is defined as an orphan receptor. Studies have shown that ROR1 plays an important role in a variety of physiological processes, including regulating cell division, proliferation, migration, and cell chemotaxis by recognizing the non-canonical WNT signaling pathway mediated by WNT protein.

14  ROS receptor

ROS receptor is a receptor tyrosine kinase encoded by the proto-oncogene c-ROS, and its ligand is unknown. ROS gene rearrangement is found in many malignant tumors such as glioblastoma and non-small cell lung cancer. It causes the continuous activation of kinases, up-regulates a variety of downstream signal pathways, and leads to continuous cell proliferation. In addition, the ROS gene also has fusion mutations with multiple genes.

(source:internet, reference only)

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