Receptor Tyrosine Kinases (RTKs)

Receptor Tyrosine Kinases (RTKs) Background

About Receptor Tyrosine Kinases (RTKs)

Receptor Tyrosine Kinases (RTKs) are a type of cell surface receptors that play a crucial role in various cellular processes, including cell growth, differentiation, survival, and metabolism. They are a family of transmembrane proteins that transmit signals from the extracellular environment to the inside of the cell, regulating numerous physiological and pathological processes.

RTKs are characterized by their structure, which consists of three main components: an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. The extracellular domain is responsible for binding specific ligands, such as growth factors or hormones, which trigger receptor activation. The intracellular domain possesses kinase activity, which allows it to phosphorylate specific tyrosine residues within the receptor itself and other downstream signaling molecules.

Upon ligand binding, RTKs undergo dimerization, where two receptor molecules come together to form an active complex. This dimerization leads to activation of the intracellular kinase domains, resulting in the phosphorylation of tyrosine residues on the receptors. Phosphorylated tyrosine residues serve as docking sites for various signaling molecules, initiating a cascade of intracellular signaling events.

These signaling pathways activated by RTKs are diverse and complex, involving various downstream molecules and effectors. They include the activation of protein kinases, such as Ras, Raf, and MAPK, as well as the recruitment and activation of adaptor proteins, such as Grb2 and Shc. These downstream effectors transmit the signal to different cellular compartments, leading to changes in gene expression, cytoskeletal rearrangements, and alterations in cell behavior and function.

The dysregulation of RTK signaling has been implicated in numerous diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. Mutations or aberrant activation of RTKs can lead to uncontrolled cell growth, survival, and proliferation, contributing to the development and progression of cancer (shown in Fig.2). Therefore, RTKs have become important targets for therapeutic interventions, and several drugs have been developed to specifically inhibit their activity in cancer treatment.

In summary, RTKs are a family of cell surface receptors that play critical roles in cellular signaling and control various physiological processes. Their activation by ligand binding triggers intracellular signaling cascades, leading to changes in gene expression and cell behavior. Understanding the functions and dysregulation of RTKs is important for elucidating disease mechanisms and developing targeted therapies.

Types of RTKs

Receptor tyrosine kinases (RTKs) represent a family of integral membrane proteins exemplified in humans by 58 proteins divided into 20 subfamilies. These include the epidermal growth factor receptor (ErbB), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and insulin-like receptor (IR) families (Fig.1):

  1. EGF receptor family, also known as ErbB receptor family: EGFR, ERBB2, ERBB3, ERBB4
  2. Insulin receptor family: INSR, IGFR
  3. Platelet-derived growth factor (PDGF) receptor family: PDGFRα, PDGFRβ, M-CSFR, KIT, FLT3L
  4. VEGF receptors family: VEGFR1, VEGFR2, VEGFR3
  5. Fibroblast growth factor (FGF) receptor family: FGFR1, FGFR2, FGFR3, FGFR4
  6. CCK receptor family: CCK4
  7. Nerve growth factor (NGF) receptor family: TRKA, TRKB, TRKC
  8. HGF receptor family: MET, RON
  9. Eph receptor family: EPHA1 to 6, EPHB1 to 6
  10. AXL receptor family: AXL, MER, TYRO3
  11. TIE receptor family: TIE, TEK
  12. RYK receptor family: RYK
  13. DDR receptor family: DDR1, DDR2
  14. RET receptor family: RET
  15. ROS receptor family: ROS
  16. LTK receptor family: LTK, ALK
  17. Receptor tyrosine kinase-like orphan receptor family, ROR receptor family: ROR1, ROR2
  18. MuSK receptor family: MUSK
  19. LMR receptor: AATYK1, AATYK2, AATYK3
  20. Undetermined: RTK106

Fig.1 Overview of the domain architecture of the 20 human RTK families. (Critchley WR, et al., 2018)Fig.1 Overview of the domain architecture of the 20 human RTK families. (Critchley WR, et al., 2018)
Each RTK contains five fundamental structures: an extracellular ligand-binding domain, a short helical transmembrane region, a juxtamembrane region, cytoplasmic domain with tyrosine kinase activity and a flexible C-terminal tail region. The extracellular ligand-binding domain displays significant variability between families, with notable additions of motifs rich in glycine, cysteine or leucine and immunoglobulin-like domains amongst others. The insulin receptor family differs from the rest due to its pre-assembled multimeric complex.

Signal Pathways Mediated by RTKs and Their Basic Patterns

Receptor tyrosine kinases (RTKs) exist as monomers without binding to signaling molecules and are inactive. Upon binding of a signaling molecule to the extracellular domain of the receptor, two monomeric receptor molecules form a dimer on the membrane, bringing the intracellular domains of the two receptors into contact, activating their protein kinase function, thus resulting in the phosphorylation of tyrosine residues in the intracellular domain. Phosphorylation causes the assembly of the intracellular domain into a signaling complex. The just-phosphorylated tyrosine sites immediately become binding sites for intracellular signaling proteins, potentially activating 10-20 different intracellular signaling proteins upon binding to the phosphorylated sites on the receptor. The signaling complex, through various signal transduction pathways, amplifies information and activates a series of biochemical reactions within the cell, or integrates different pieces of information to elicit a comprehensive cellular response (such as cell proliferation).

Signal Transduction

Ligand binding to extracellular regions typically induces or stabilizes receptor dimerization, leading to trans-phosphorylation of tyrosines in the cytoplasmic portions of each receptor monomer by its partner receptor, hence transmitting the signal across the membrane. Phosphorylation of specific tyrosine residues within the activated receptor provides binding sites for proteins containing SH2 domains and phosphotyrosine-binding (PTB) domains. Proteins containing these domains include Src and phospholipase Cγ. Phosphorylation and activation of these proteins, which bind to the receptor, initiate the signaling transduction pathway. Other proteins that interact with the activated receptor act as adaptor proteins and do not possess intrinsic enzymatic activity. These adaptor proteins link RTK activation to downstream signal transduction pathways, such as the MAP kinase signaling cascade. One crucial signaling pathway includes the tyrosine kinase receptor c-met, which is essential for the survival and proliferation of migrating myoblasts during muscle development. Lack of c-met disrupts secondary myogenesis and, similar to LBX1, prevents the formation of limb muscle tissue. The localized action of FGF (fibroblast growth factor) and its RTK receptor is classified as paracrine signaling. Due to the phosphorylation of multiple tyrosine residues by RTK receptors, they can activate multiple signaling pathways.

Available Resources for Receptor Tyrosine Kinases (RTKs)

  • Creative BioMart provides a variety of products related to RTK, including recombinant proteins, cell and tissue lysates, protein pre-coupled magnetic beads, etc.
  • Whether you are in academic research or biopharmaceuticals, we can meet your needs. We have extensive experience and expertise and can tailor services to your specific requirements.
  • In addition to products and customized services, we also provide a wide range of resources for your reference, such as involved pathways, protein function, interacting proteins, articles, research, and others related to RTKs, to help you better understand and apply RTK-related knowledge.

Our Featured Products

Active Recombinant Human EGFR protein, Fc-tagged, APC labeled
Active Recombinant Human EGFR Protein, His-GST-tagged, Alexa Fluor 488 conjugated
Recombinant Human INSR, His tagged
Recombinant Human PDGFRA, GST-tagged
Recombinant Human PDGFRB Protein, His-tagged, FITC conjugated
Active Recombinant Human FGFR1 Protein, His/GST-tagged, Alexa Fluor 555 conjugated
Active Recombinant Human MET Protein, Fc/His-tagged, Alexa Fluor 555 conjugated
Recombinant Human MET Protein, His/GST-tagged, Alexa Fluor 488 conjugated
Recombinant Human ERBB3 Protein, Fc-tagged, Alexa Fluor 555 conjugated

If you have any questions, requirements, or cooperation intentions, please feel free to contact us. We very much look forward to working with you and helping you achieve research and commercial success.

Fig.2 Schematic representation of receptor tyrosine kinase and downstream signaling pathways. (Regad T, 2015)Fig.2 Schematic representation of receptor tyrosine kinase and downstream signaling pathways. (Regad T, 2015)

References:

  1. Critchley WR, Pellet-Many C, Ringham-Terry B, Harrison MA, Zachary IC, Ponnambalam S. Receptor Tyrosine Kinase Ubiquitination and De-Ubiquitination in Signal Transduction and Receptor Trafficking. Cells. 2018 Mar 15;7(3):22.
  2. Regad T. Targeting RTK Signaling Pathways in Cancer. Cancers (Basel). 2015 Sep 3;7(3):1758-84.
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