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

Table 2. Summary of cancer-associated tyrosine kinases 3.2. Src structure and regulatory mechanism
Class of tyrosine kinase Cancer type and mechanism The primary function of the Src is to transmit the external
EGFR (HER1, HER2, Epithelial tumors in lung, breast, and signal to the cell interior by phosphorylating tyrosine
HER3, HER4) colon 17,70 residues on substrates, mainly downstream of RTKs and
95
VEGFR-1 to -3 Regulate angiogenesis and cell migration integrins. Src kinases are crucial in various cellular
in tumors 21,71,72 processes, such as cell proliferation, adhesion, migration,
42
FGFR-1 to -4 Tissue cancer 22 and more. The Src kinase’s complicated regulation is due
TRKA, TRKB, TRKC Neuronal cancer 25,73 to its complex structure. The structures of SH3, SH2, and
(NTRK family) SH1 KDs of Src kinases have been extensively studied and
RET Implicated in multiple cancers 35,74 reviewed elsewhere. The Src KD features a characteristic
RYK Contributes to tumorigenesis 36,75 bilobed architecture comprising a small N-terminal lobe
and a large C-terminal lobe. The residues 267–337 and
DDR1, DDR2 Regulate adhesion, invasion, and survival 341–520 make up these lobes, respectively. The N-lobe
in collagen-rich tumors 37,76,77 predominantly anchors and orients ATP, featuring a
ROS Present in many cancer types 38 G-rich loop, which is a part of the nucleotide-phosphate
LMTK/LMR Cancer-linked; influences proliferation, binding site. The N-lobe is mostly composed of antiparallel
migration 78,79 β-sheet structures. The C-lobe is predominantly
96
ALK, LTK Fusion-driven cancers (e.g., ALK fusions composed of a helix, responsible for binding the protein
in lymphoma, lung cancer 40,41,80 substrates and contributing to the ATP-binding site. The
STYK Involved in proliferation and survival; catalytic site of Src is situated in a cleft between these two
emerging as a cancer target 81 lobes; they open and close during ATP hydrolysis. The
97
Ack1 Promotes tumor growth, chemoresistance, dynamic conformational switch regulates ATP binding
gene amplification 45,82 and ADP release; the open form is required to allow
JAK1, JAK2, JAK3, TYK2 Crucial for immune modulation in ATP to its catalytic pocket and release ADP; the closed
cancers 83 form is important to bring residues into the catalytically
Fes, Fer Signal for migration, survival; linked to active form. The Src kinase regulation precisely involved
oncogenesis 84
the coordination of non-regulatory SH2 and SH3
FAK family Adhesion, motility; high expression in domains and a regulatory KD. 89,97 In the autoinhibitory
aggressive tumors 85,86
Src family Major signaling mediators; upregulated in conformation, the SH2 domain binds to phosphotyrosine-
containing motifs, precisely, phosphorylated Tyr527 in the
various tumors 60 89,97
Abl, Arg Leukemia 67,87,88 C-terminal tail of Src and stabilizes the conformation.
The SH3 domain interacts with a polyproline-rich motif
Syk, Zap70 Hematologic cancers 69 situated between the SH2 and KDs. This interaction
Abbreviations: EGFR: Epidermal growth factor receptor; HER: Human positions SH2–SH3 domains as a compact structural
epidermal growth factor receptor; VEGFR: Vascular endothelial growth unit, which further prevents the movement of the KD
factor receptor; FGFR: Fibroblast growth factor receptor;
NTRK: Neurotrophic tyrosine receptor kinases; TRK: Tropomyosin and, consequently, locks the Src in its inactive state. The
receptor kinases; RYK: Receptor tyrosine kinase; DDR: Discoidin activation loop (residues 404–418) conformations in
domain receptor; ROS: Reactive oxygen species; LMTK/LMR: Lemur the KD dictate the active and inactive state of the Src
receptor kinases; ALK: Anaplastic lymphoma kinase; LTK: Leukocyte kinase. In the inactive Src kinase, the activation loop
tyrosine kinase; STYK: Serine/threonine/tyrosine kinase; Fes: Feline forms a short a-helix between N- and C-lobes, known
sarcoma; Fer: Feline sarcoma-related; JAK: Janus Kinase; FAK: Focal 89,97
adhesion kinase; Src: Sarcoma; Abl: Abelson; Syk: Spleen tyrosine as the A-loop helix. As a result, the Tyr416 residue
kinase; RET: Rearranged during transfection; Ack1: Activated Cdc42- side chain is buried between the N- and C-lobes, and
associated kinase; Arg: Abl-related gene; Zap70: Zeta-chain-associated this conformational switch leads to the prevention of the
protein kinase 70. formation of a salt bridge between Lys295 and Glu310
required for enzyme activity. The autophosphorylation of
residues), a short (SH2 ~100 residues), SH2 kinase linker, Tyr416 disrupts the autoinhibitory state of the Src kinase,
catalytic tyrosine-protein KD (Src Homology 1 [SH ), and leading to an extended conformational switch in the
1
a short intrinsically disordered C-terminal tail. While the activation loop and alignment of catalytic residues such as
KD has a catalytic function, the SH2 and SH3 domains are Asp386 and Asp404. Asp386 residue acts as a catalytic base
commonly involved in non-catalytic regulatory properties. for the tyrosine substrate, whereas Asp404 interacts with
However, all three domains are essential in signal magnesium ions that stabilize ATP. Numerous studies on
transduction 8,90-94 (Figure 1D and E). Src have revealed that SH2 and SH3 domains are critical

Volume 2 Issue 3 (2025) 25 doi: 10.36922/IMO025200022