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

IGF1 and IGF2 are capable of binding to and activating the TIE2, regulates angiogenesis and lymphangiogenesis. The
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IGF1R transmembrane receptor kinase. However, when erythropoietin-producing hepatocellular (Eph) receptor
IGF2 binds, it does not activate any downstream signaling family (EphA1–A10, EphB1–B6) controls angiogenesis,
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pathways because the IGF2R lacks the kinase structural cell migration, patterning, and neuronal formation. The
domain necessary for this activation. Platelet-derived RET receptor, activated by glial cell-derived neurotrophic
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growth factor receptor (PDGFR), colony-stimulating factor ligands, is crucial for cell proliferation, neuronal
factor 1 receptor (CSF1R), KIT proto-oncogene receptor, navigation, migration, and differentiation. The receptor
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and FMS-like tyrosine kinase 3 receptors are critical for tyrosine kinase is characterized by extracellular Wnt-
various cellular processes. Platelet-derived growth factor binding domains and is closely associated with Wnt
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(PDGF) is essential for tissue growth, division, and blood signaling. The discoidin domain receptor (DDR) family,
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vessel formation. CSF1R, secreted by cancer cells to evade which includes DDR1 and DDR2, regulates cell adhesion,
immune detection, promotes the growth and recruitment proliferation, and metalloproteinase expression. DDR1
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of tumor-associated myeloid cells, contributing to poorer also promotes tumor cell invasion and enhances the survival
survival in many cancers. The vascular endothelial growth of tumor stem cells in collagen-rich environments. The
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factor (VEGF) receptor (VEGFR) family—VEGFR-1, reactive oxygen species (ROS) receptor family is present in
VEGFR-2, and VEGFR-3—regulates processes such as various malignant tumors, making it a promising target for
cell migration, angiogenesis, and metabolic homeostasis. anticancer drugs. Lemur receptor kinases are linked to
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Likewise, the fibroblast growth factor receptor (FGFR) cancer and influence multiple signaling pathways involved
family, including FGFR1-4, plays a role in tissue repair, in cell proliferation, migration, and invasiveness. The
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regeneration, and the growth and differentiation of cells anaplastic lymphoma kinase (ALK) receptor family
during development and organ formation. Protein includes ALK and leukocyte tyrosine kinase. ALK gene
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tyrosine kinase-like 7 and colon carcinoma kinase 4 fusion is linked to the formation of various tumors. In
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receptors are involved in epithelial cell polarization and addition, the serine/threonine/tyrosine kinase receptor
brain structure formation. These receptors are catalytically plays a role in cellular processes such as proliferation,
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active protein kinases and play roles in the Wnt and VEGF differentiation, and survival. 12
signaling pathways. The neurotrophin receptor kinases Non-receptor TKs (NRTKs) include Ack, Janus
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family includes tropomyosin receptor kinases (TRK) Kinase (Jak), feline sarcoma (Fes), focal adhesion kinase
A, TRKB, and TRKC receptors, which are vital for the (Fak), Tec, sarcoma (Src), C-terminal Src kinase (Csk),
proliferation and migration of the nervous system. TRKA 42
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responds to nerve growth factor, TRKB to brain-derived Abelson (Abl), and spleen tyrosine kinase (Syk) kinases.
neurotrophic factor, and TRKC to neurotrophin-3. The These NRTKs typically consist of the N-terminal kinase
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domain (KD), which is around 300 residues long, and
RTK-like orphan receptor (ROR) family includes ROR1 the C-terminal region, which contains several functional
and ROR2 receptors. ROR1 acts as a substitute receptor domains. NRTKs share significant sequence similarity
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and co-receptor for Wnt signaling, regulating cell division,
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polarity, and tissue maintenance. In contrast, ROR2’s within their KDs, and their catalytic domains are like those
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role in tumor development varies depending on the of Ser/Thr protein kinases. In addition to their catalytic
domains, NRTKs also feature non-catalytic domains that
tumor type or stage; it can either repress or activate tumor regulate their activity. The classification of NRTKs into
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growth through atypical Wnt signaling. The muscle-
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specific kinase receptor is essential for the formation distinct families is based on molecular analysis of their
and organization of neuromuscular junctions in skeletal domain structures, variations in amino acid sequences,
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muscle. The hepatocyte growth factor (HGF) receptor and genomic organization of the KDs. Below is a brief
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overview of the most common NRTK families.
family includes mesenchymal-epithelial transition (MET)
factor and Recepteur d’Origine Nantais receptors. When The activated Cdc42-associated kinase (ACK) is a large
HGF binds to MET, it activates the proliferation, migration, protein of 120 kDa whose kinase activity can be mediated
and morphogenesis of epithelial cells. The TYRO3, by the phosphorylation of its tyrosine residues. Ack1 is a
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AXL, and MER receptors are activated by the vitamin non-receptor tyrosine kinase with a unique multidomain
K-dependent proteins Gas6 and protein S, regulating cell structure, including an Src homology 3 (SH3) and Cdc42/
proliferation, survival, adhesion, and migration. They Rac interactive binding (CRIB) domain that regulates
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also have anti-inflammatory properties and are implicated cellular functions such as migration and adhesion and
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in carcinogenesis in various malignancies. The tyrosine plays a critical role in cancer progression. Furthermore,
kinase with immunoglobulin (Ig)-like and EGF-like Ack1 promotes tumor growth, resistance to chemotherapy,
domains (TIE) receptor family, consisting of TIE1 and and recurrence through gene amplification, mutations,
Volume 2 Issue 3 (2025) 23 doi: 10.36922/IMO025200022