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

and epigenetic regulation. The Jak/Janus family consists NLS is a bipartite motif that enables nuclear targeting and
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of four kinases (JAK1, JAK2, JAK3, and TYK2), each with functional regulation in the cell. The Abl family includes
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two KDs, one functional and one pseudo-kinase. These Abl and Arg kinases, which are widely expressed, with
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kinases are activated by cytokine receptor ligation, leading high levels in the thymus, spleen, and brain. Both kinases
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to transphosphorylation and downstream signaling. have structures similar to Src family members but feature
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JAKs play crucial roles in immune cell regulation and a unique C-terminal actin-binding domain and nuclear
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tumor development through the JAK-STAT pathway. JAK3 localization signals. Abl activation, through mutation or
is primarily found in hematopoietic cells, while other JAKs phosphorylation, is linked to leukemia and solid tumors
are involved in diverse cytokine signaling processes. Fes such as brain, lung, and prostate cancers. The Syk family
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and Fes-related (Fer) kinases are a subgroup of NRTKs with includes Syk and zeta-chain-associated protein kinase
similarities to viral oncogenes from Fes virus and avian 70 (ZAP70) kinases, which share a similar structure
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Fujinami poultry Src virus. Fes kinases have a unique containing two SH2 domains followed by a catalytic KD.
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Fes/CIP4 homology (FCH) domain, coiled-coil motifs, an These kinases are cytosolic proteins lacking fatty acid
Src homology 2 (SH2) domain, and a C-terminal KD. Fes modification sites, and upon cell stimulation, Syk and
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and Fer kinases are implicated in cancer progression, with Zap70 translocate to immune receptor complexes at the
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Fes playing a role in cell signaling pathways that influence membrane to trigger downstream signaling. A tabular
cell migration, proliferation, and survival, contributing to representation of kinases that play a significant role in
tumorigenesis. The Fak family includes Fak, Pyk2, Cak- various cancer types is represented in Table 2.
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beta, Cadtk, Raftk, and Fak2, with varying expression in
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organs such as the brain, liver, and hematopoietic cells. 3. Structural and regulatory mechanisms of
Fak family kinases feature a FERM domain that mediates TKs
interactions with integrins and RTKs and a C-terminal FAT PTKs play a critical role in cellular signaling pathways, and
region involved in focal adhesion targeting. Fak plays a their catalytic activity is tightly regulated. Numerous atomic
crucial role in tumor cell signaling, including transcriptional structures of PTKs reported in the literature have provided
regulation within the tumor microenvironment (TME). structural and mechanistic insights into the regulation of
Overexpression of Fak is linked to aggressive cancers, both receptor and non-receptor PTKs. As several PTKs
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including breast, colon, and ovarian, and is associated with are available in the Protein Data Bank (PDB), the current
metastasis and poor prognosis. The Tec family consists review will focus on EGFR kinase as a representative of
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of five NRTK members, including Tec, Itk, Btk, Txk, and receptor PTK and Src for non-receptor PTKs.
Bmx, characterized by several conserved domains, such
as a pleckstrin homology domain involved in membrane 3.1. PTK domain architecture
association, a Tec homology domain, which includes a RTKs are composed of three main regions: a large
zinc-binding region, a SH3 domain that regulates protein- extracellular region, which binds to polypeptide ligands,
protein interactions, an SH2 domain that interacts with a transmembrane helix, and a cytoplasmic region, which
phosphorylated tyrosine residues, and a catalytic KD. Tec possesses tyrosine kinase activity. The extracellular region
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kinases are involved in immune cell signaling, with specific of RTKs is classically composed of a diverse array of distinct
expression in T, B, and natural killer cells. The Src family globular domains, including Ig-like domains (domain-1),
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is one of the largest NRTK families that include eight fibronectin type-III-like domains (domain-2), cysteine-rich
members, such as Fyn, Yes, Fgr, and Lyn, divided into two domains (domain-3), and EGF-like domains (domain-4).
subfamilies: Src-A (Fgr, Fyn, Src, Yes) and Src-B (Blk, Hck, In the case of EGFR kinase, the extracellular region includes
Lck, Lyn). These kinases share a similar structure with Src amino acids 1–165 (domain-1), 166–310 (domain-2),
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homology 4 (SH4), SH3, SH2, and KDs but differ in their 311–480 (domain-3), and 481–621 (domain-4). However,
C-terminal regulatory regions. Src family kinases (SFKs) the cytosolic region of RTKs domain organization is simple,
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are involved in diverse cellular processes, with distinct consisting of the juxtamembrane region (amino acids 643–
expression patterns in hematopoietic and other tissues. 685), immediately followed by the transmembrane helix, a
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Fyn-related kinase (FRK) is a member of the breast tumor tyrosine KD (amino acids 686–952), and a carboxy region
kinase family, closely related to SFKs. FRN kinases feature (amino acids 953–1186) (Figure 1A-C). Unlike RTKs, the
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an SH3, SH2, and KD but lack the N-myristoylation extracellular and transmembrane regions in NRTKs are
site, which prevents membrane localization and allows absent, and most of the NRTKs are present in the cytosol.
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nuclear localization. Unique to FRK and inhibitory The NRTKs comprise intrinsically disordered regions (IDR)
tyrosine kinase (IYK) kinases is the presence of a nuclear and folded domains. At the N-terminus IDR region, unique
localization signal (NLS) within the SH2 domain. The myristoylated SH4 fragments, a smaller SH3 domain (~60
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Volume 2 Issue 3 (2025) 24 doi: 10.36922/IMO025200022