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Innovative Medicines & Omics Tyrosine kinases: Structure, mechanism, and therapeutics

making them critical targets for therapeutic interventions, Table 1. RTKs’ classification is based on the sequence of the
particularly in cancer treatment. 6,7 kinase domain
The PTK family is diverse, with members varying in Class Family Receptors
structure and function. These kinases are classified into I EGF/ EGFR, ErbB2/HER2, ErbB3/HER3,
8
two major subgroups: receptor TKs (RTKs) and non- ErbB ErbB4/HER3
receptor TKs (NRTKs). RTKs are membrane-bound II Ins InsR, IGF1R, InsRR
7,9
enzymes that transmit extracellular signals such as growth III PDGF PDGFRα, PDGFRβ, CSF1R, KIT, FLT3
factors, cytokines, and hormones to the cytoplasm and
nucleus, initiating a cascade of cellular responses. The key IV VEGF VEGFR1/Flt1, VEGFR2/KDR,
4,7
VEGFR3/Flt4
function of RTKs is to rapidly and reversibly phosphorylate
protein substrates, which leads to alterations in protein V FGF FGFR1, FGFR2, FGFR3, FGER4
conformation and interaction, driving various cellular VI PTK7 PTK7/CCK4
processes such as growth and survival. On the other hand, VII TRK TRKA, TRKB, TRKC
10
NRTKs lack extracellular and transmembrane domains VIII ROR ROR1, ROR2
and are found in the cytoplasm or nucleus. These kinases IX MuSK MuSK
are involved in mediating intracellular signals, often in X HGF MET, MST1R (RON)
response to receptor-dependent activation at the cell XI TAM AXL, MER, TYRO3
membrane. While RTKs and NRTKs function similarly
7,11
by regulating crucial cellular processes, including cell XII TIE TIE1, TEK (TIE2)
division, growth, and immune responses, their structures XIII Eph EphA1-8, EphA10, EphB1-4, EphB6
are strikingly distinct. Due to their essential roles in XIV RET RET
7,12
cellular signaling, both RTKs and NRTKs are critical in XV RYK RYK
the regulation of various physiological functions and are XVI DDR DDR1, DDR2
often implicated in the progression of cancers when their XVII ROS ROS
activation becomes dysregulated. The discovery of the Src XVIII LMR LMR1, LMR2, LMR3
13
oncogene and the identification of the epidermal growth
factor receptor (EGFR) as the first RTK laid the foundation XIX ALK LTK, ALK
for understanding the role of TKs in cancer. So far, XX STYK1 STYK1
14
over 90 TKs have been identified, and these enzymes are Note: Adapted and modified from ref. 16
now recognized as pivotal players in cellular signaling Abbreviations: RTKs: Receptor tyrosine kinases; EGF: Epidermal
circuits that contribute to cancer development. Hence, growth factor; EGFR: Epidermal growth factor receptor; HER2: Human
15
epidermal growth factor receptor; Ins: Insulin; InsR: Insulin receptor;
TKs represent a significant portion of oncoproteins, PDGF: Platelet-derived growth factor; PDGFR: Platelet-derived
and targeting these for therapeutic development is a growth factor receptor; CSF1R: Colony-stimulating factor 1 receptor;
promising strategy in the treatment of cancers associated KIT: KIT Proto-oncogene receptor; FLT3: FMS-like tyrosine kinase 3;
with their dysregulation. This review focuses on a VEGF: Vascular endothelial growth factor; VEGFR: Vascular
6
deeper structural and mechanistic understanding and endothelial growth factor receptor; FGF: Fibroblast growth factor;
FGFR: Fibroblast growth factor receptor; PTK7: Protein tyrosine
therapeutic implications of PTKs, using EGFR and Src as kinase-like 7; CCK4: Colon carcinoma kinase 4; TRK: Tropomyosin
representative models of RTKs and NRTKs, respectively. receptor kinases; ROR: RTK-like orphan receptor; MuSK: Muscle-
In addition, the current review also emphasizes recent specific kinase, HGF: Hepatocyte growth factor; MET: Mesenchymal-
developments aimed at overcoming resistance to tyrosine epithelial transition; MST1R: Mesenchymal-epithelial transition
kinase inhibitors (TKIs). 1 receptor; RON: Recepteur d’Origine Nantais; TAM: TYRO3,
AXL, MER; TIE: tyrosine kinase with immunoglobulin-like and
2. Classification of PTKs EGF-like domains; Eph: Erythropoietin-producing hepatocellular;
RYK: Receptor like tyrosine kinase; DDR: Discoidin domain receptor;
As described above, PTKs are primarily classified as RTKs ROS: Reactive oxygen species; LMR: Lemur receptor kinases;
and NRTKs. Based on the composition of the extracellular ALK: Anaplastic lymphoma kinase; LTK: Leukocyte tyrosine kinase;
9
STYK: Serine/threonine/tyrosine kinase; ErbB: Erythroblastic leukemia
regions, the 58 identified RTKs in humans are further viral oncogene homolog; RET: Rearranged during transfection.
categorized into 20 distinct families. A brief introduction
and description of each of the distinct RTK families is and HER4. These receptors are often overexpressed in
presented in Table 1. epithelial tumors, such as colorectal, head and neck, non-
17
The epidermal growth factor family (EGF) includes small cell lung, breast, pancreatic, and renal cell cancers.
epidermal growth factor receptor (EGFR), human The insulin growth factor (IGF) and insulin receptor (InsR)
epidermal growth factor receptor (HER)1, HER2, HER3, family consists of the IGF1R and InsR receptors. Both

Volume 2 Issue 3 (2025) 22 doi: 10.36922/IMO025200022