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Tyrosine-protein kinase Lck

Tyrosine-protein kinase Lck (Lck), encoded by the LCK gene on 1p35.2, is a non-receptor Src family tyrosine kinase essential for T-cell development, selection, maturation, and function. Primarily expressed in lymphoid tissues such as the , lymph nodes, and , Lck serves as a key initiator of (TCR) signaling by associating with the coreceptors and and phosphorylating immunoreceptor tyrosine-based activation motifs (ITAMs) on the TCR complex upon stimulation. This phosphorylation cascade activates downstream effectors like ZAP-70 and LAT, amplifying immune responses critical for adaptive immunity. Structurally, Lck consists of an N-terminal unique domain for membrane anchoring via myristoylation and palmitoylation, followed by Src homology 2 (SH2) and Src homology 3 (SH3) domains that mediate protein-protein interactions, and a C-terminal domain responsible for activity. Its activity is tightly regulated by : activating at Tyr-394 in the activation loop enhances function, while inhibitory at Tyr-505 by Csk promotes an autoinhibited conformation. Lck localizes primarily to the plasma membrane and endosomal compartments in T cells, enabling rapid responses to extracellular signals. Beyond its canonical role in T-cell activation, Lck influences broader immune processes, including T-cell migration, production, and interactions with pathogens such as HIV-1, where it binds viral proteins like Nef to modulate infectivity. Dysregulation of Lck has been implicated in immunodeficiencies, such as (SCID) due to loss-of-function mutations, as well as in malignancies like T-cell leukemias and lymphomas, where it acts as a proto-oncogene promoting uncontrolled proliferation. These features position Lck as a promising therapeutic target for autoimmune diseases, cancers, and infectious disorders, with recent advances including molecular glue degraders for as of 2025.

Structure and Localization

Protein Domains and Architecture

Tyrosine-protein kinase Lck is a 58 kDa non-receptor tyrosine kinase encoded by the LCK gene located on human 1p35.2. As a prototypical member of the Src family kinases (SFKs), Lck possesses a conserved modular comprising an N-terminal unique domain, Src homology 3 (SH3) and Src homology 2 (SH2) regulatory domains, a flexible linker, and a C-terminal catalytic kinase domain. This organization enables Lck to integrate membrane localization, protein-protein interactions, and phosphotransfer activity essential for its role in T-cell signaling. The N-terminal unique domain spans residues 1–58 and includes sites for post-translational lipid modifications: myristoylation at glycine 2 and palmitoylation at cysteines 3 and 5, which facilitate plasma membrane association. Adjacent to this is the SH3 domain (residues 59–119), a compact β-barrel structure that recognizes proline-rich motifs to mediate intramolecular and intermolecular interactions. The (residues 125–222) follows, featuring a phosphotyrosine-binding pocket that allows recognition of phosphorylated substrates and regulatory sites. These regulatory domains are connected by a short linker region (residues 223–250) to the bilobal domain (residues 251–509), which harbors the ATP-binding site and catalytic core; notable residues include tyrosine 394 in the activation loop for autophosphorylation and tyrosine 505 in the C-terminal for inhibitory phosphorylation. Crystal structures have elucidated the conformational dynamics of Lck's domains. The SH3–SH2 fragment (PDB: 1LCK) reveals how these modules pack together in a compact assembly, with the SH3 domain binding proline-rich sequences and the SH2 domain engaging phosphotyrosine ligands, facilitating autoinhibitory clamping over the kinase domain in the inactive state. The activated kinase domain structure (PDB: 3LCK) demonstrates an open activation loop at tyrosine 394, exposing the catalytic cleft and highlighting conserved features like the P-loop and catalytic lysine, while underscoring Lck's structural similarity to other eukaryotic kinases. Compared to other SFKs, Lck's architecture is highly conserved, but its unique domain—one of the shortest at ~60 residues—lacks certain regulatory inserts present in c-Src (e.g., alternative splicing variants) and features T-cell-specific motifs, such as a conserved CxxC motif that forms a zinc clasp with the CXCP motifs in the coreceptors CD4 and CD8, distinguishing its localization and specificity.00147-9)

Membrane Association and Modifications

The N-terminal unique domain of Lck undergoes critical post-translational lipid modifications that anchor it to the plasma membrane. Myristoylation occurs at residue 2, facilitated by N-myristoyltransferase, which provides initial attachment to the inner leaflet of the bilayer.47435-2/fulltext) This is followed by dual palmitoylation at residues 3 and 5, mediated by palmitoyl acyltransferases such as DHHC family members, which enhances stable membrane tethering through hydrophobic interactions. These modifications are essential for Lck's proximity to the complex, as myristoylation alone is insufficient for robust binding, while the combination ensures efficient localization.47435-2/fulltext) In T cells, these lipid anchors direct Lck to glycosphingolipid-enriched microdomains, commonly known as lipid rafts, which are - and sphingolipid-rich regions of the plasma membrane. This localization facilitates Lck's clustering with and co-receptors, promoting coordinated immune signaling initiation upon recognition. The SH3 and SH2 domains of Lck contribute to intramolecular following these membrane associations, maintaining basal inactivity until stimulation. Palmitoylation of Lck is dynamically reversible, allowing redistribution in response to T cell receptor signaling. Upon activation, depalmitoylation by thioesterases such as APT1 occurs rapidly, leading to Lck dissociation from rafts and modulation of signaling intensity. This cycle of palmitoylation and depalmitoylation links Lck's localization to T cell activation states, enabling transient enhancements in activity. studies have demonstrated the functional necessity of these associations. Substitution of glycine 2 with alanine blocks myristoylation and subsequent palmitoylation, resulting in cytoplasmic retention and complete abolition of signaling in Lck-deficient s. Similarly, mutating cysteines 3 and 5 to serines prevents palmitoylation, disrupting and eliminating downstream T cell activation, underscoring the irreplaceable role of dual acylation.47435-2/fulltext)

Function in Immune Signaling

Role in T Cell Receptor Activation

Lck, a Src family tyrosine kinase, was first identified in 1985 as a lymphocyte-specific protein encoded by the lskT locus, through from the murine LSTRA, where it was found overexpressed and rearranged. Subsequent studies in 1988 confirmed its association with the T cell co-receptors and in normal T lymphocytes, establishing its role in early T cell signaling. Upon , the (TCR) engages peptide-major histocompatibility complex (pMHC), bringing or co-receptors into proximity with the TCR complex; Lck, non-covalently bound to the cytoplasmic tails of these co-receptors via a clasp structure formed by motifs in Lck's unique N-terminal domain and the co-receptor tails, is thereby positioned to initiate signaling. This association, mediated by the conserved CxC motif in / and CxxC in Lck, coordinates ions to stabilize the interaction, ensuring Lck's availability near the TCR. Lck then phosphorylates residues within immunoreceptor tyrosine-based activation motifs (ITAMs) on the cytoplasmic domains of CD3 ζ-chains and other TCR subunits, such as CD3ε and CD3δ. These events create docking sites for downstream effectors; for instance, bis-phosphorylated ITAMs on the ζ-chain recruit the ZAP-70 via its SH2 domains. Basal Lck activity establishes a signaling that determines T cell sensitivity to , with approximately 50% of Lck in an active state in effector memory T cells compared to less than 20% in central memory T cells, thereby tuning responsiveness based on differentiation state. Lck is essential for thymic T cell maturation, as demonstrated by knockout studies showing a profound block in thymocyte development at the double-positive stage, impairing both positive and negative selection processes critical for generating a self-tolerant T cell repertoire.

Downstream Signaling Pathways

Upon TCR engagement, Lck phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) on the CD3 and ζ-chains of the T cell receptor complex. These phosphotyrosines serve as docking sites for the SH2 domains of ZAP-70 (or Syk in some contexts), recruiting it to the plasma membrane. Lck subsequently phosphorylates ZAP-70 at key tyrosine residues, such as Y493 and Y492, activating its kinase domain and enabling further signal propagation. Activated ZAP-70 then phosphorylates the adaptor protein LAT, creating multiple docking sites that recruit additional signaling molecules, thereby facilitating the assembly of LAT-based signalosomes at the immune synapse. These signalosomes coordinate several major downstream pathways essential for T cell effector functions. The Ras-MAPK/ERK pathway is initiated through ZAP-70-mediated activation of RasGRP1 by diacylglycerol (DAG), leading to sequential phosphorylation of Raf1, MEK1/2, and ERK1/2, which culminates in the activation of transcription factors like AP-1 to drive T cell proliferation and differentiation. Concurrently, phospholipase C-γ1 (PLC-γ1) is recruited and activated within the signalosome, hydrolyzing phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and DAG; IP3 triggers calcium release from the endoplasmic reticulum, mobilizing intracellular Ca²⁺ stores and activating calcineurin, which dephosphorylates NFAT to promote its nuclear translocation and gene expression for cytokines like IL-2. Additionally, DAG activates protein kinase C-θ (PKC-θ), which assembles the CARD11-BCL10-MALT1 (CBM) complex to stimulate IκB kinase (IKK), resulting in NF-κB nuclear translocation and enhanced T cell survival and cytokine production. Lck signaling integrates with co-stimulatory pathways, notably , to fine-tune T cell responses. Lck binds the cytoplasmic tail of via its SH2/SH3 domains, phosphorylating key tyrosines (e.g., Y209) to recruit PI3K and PDK1, which synergize with TCR signals to enhance , NFAT, and AP-1 activation, thereby promoting robust IL-2 production and mRNA stabilization. This integration is crucial for T cell , as -Lck signaling upregulates expression in regulatory T cells and supports effector T cell expansion without inducing anergy. Quantitative analyses from 2020-2024 studies using models reveal that Lck dosage critically modulates TCR signal strength, particularly in responses. For instance, reduced co-receptor-bound Lck (as in LckCA/CA mice) impairs signaling to low-affinity antigens, decreasing ERK activation and proliferation by up to 50% compared to wild-type, while sufficient "free" Lck maintains responses to high-affinity ligands; this dosage sensitivity is heightened in + T cells, where partial Lck defects lead to diminished output and impaired recall responses.

Regulation of Activity

Activation Mechanisms

The activation of Lck, a essential for T cell signaling, primarily involves the relief of autoinhibitory constraints and subsequent enhancement of its catalytic activity. A key initial step is the of the inhibitory tyrosine residue Y505 in Lck's C-terminal tail by the transmembrane CD45. This disrupts the intramolecular interaction between the and the phosphorylated Y505, thereby relieving autoinhibition and allowing Lck to adopt an open, active conformation. Studies in CD45-deficient models demonstrate that this process is critical for development and T cell activation, as the absence of CD45 leads to persistent Y505 phosphorylation and impaired Lck function. Following , Lck undergoes trans-autophosphorylation at the activating tyrosine Y394 within its domain, particularly upon (TCR) clustering during recognition. This autophosphorylation stabilizes the active conformation of the domain, significantly increasing catalytic efficiency; for instance, the Michaelis constant () for ATP is approximately 10 μM in the activated state. The process occurs intermolecularly between Lck molecules in close proximity, facilitated by TCR-induced membrane reorganization. Co-receptor engagement by or further promotes Lck activation by displacing the negative regulator C-terminal Src kinase (Csk) from the plasma membrane. Upon TCR ligation, and associate with Lck via their cytoplasmic tails, which helps exclude Csk and reduces its ability to phosphorylate Y505, thereby sustaining the open Lck conformation. Lipid rafts play a crucial role in this process by concentrating Lck, co-receptors, and activators while transiently displacing Csk, enhancing the spatial efficiency of activation. Recent research has identified additional regulators, such as the molecule CD146, which binds to Lck and promotes its autophosphorylation at Y394, particularly in contexts involving T cell motility and immune responses. In murine models, CD146 dimerization upon stimulation recruits Lck and enhances its activation, contributing to effective TCR signaling during T cell toward inflammatory sites.

Negative Regulation and Feedback

The activity of Lck is negatively by phosphorylation at tyrosine 505 (Y505) by the C-terminal Src kinase (Csk), which induces an intramolecular interaction between the phosphorylated Y505 and the SH2 domain, stabilizing a closed, inactive conformation of the kinase. This inhibitory maintains Lck in a basal inactive state in resting T cells, preventing aberrant signaling. Csk is recruited to the plasma membrane via adaptors such as PAG, facilitating this regulatory . Additional negative control occurs through the recruitment of protein phosphatases, including SHP-1 and PTPN22 (also known as LYP or PEP), which dephosphorylate the activating Y394 residue on Lck, thereby reducing its kinase activity. SHP-1 is particularly effective at targeting Y394 in activated T cells, while PTPN22 contributes to fine-tuning Lck activity during antigen receptor signaling. Furthermore, the Cbl promotes Lck ubiquitination and subsequent proteasomal degradation, limiting sustained signaling by reducing Lck protein levels post-activation. The SH3 domain of Lck is essential for its interaction with Cbl, underscoring the role of domain-specific binding in this degradative pathway. Feedback inhibition involves immunoreceptor tyrosine-based inhibitory motifs (ITIMs) on co-inhibitory receptors such as PD-1, which recruit phosphatases like SHP-1 and SHP-2 upon ligation, leading to of Lck and proximal TCR signaling components. This mechanism dampens Lck-driven responses during chronic antigen exposure, promoting T cell tolerance. Spatial sequestration also contributes to negative regulation; in resting T cells, a portion of active Lck (phosphorylated at Y394) is confined to heavy detergent-resistant membrane fractions (non-raft domains) associated with CD45, which limits its access to TCR complexes, and this compartmentalization helps terminate signaling after activation by restricting Lck redistribution. CD45 exhibits a , dephosphorylating inhibitory Y505 for basal while also contributing to Y394 dephosphorylation for restraint.

Molecular Interactions and Substrates

Key Protein Interactions

Lck forms critical associations with T cell co-receptors and through a zinc clasp structure in its N-terminal unique domain, binding to the cytoplasmic tails of these co-receptors with a (Kd) of approximately 400 nM for the CD4-Lck interaction. This stable binding positions Lck near the (TCR) complex, facilitating rapid kinase recruitment during . Lck also interacts with the transmembrane phosphatase CD45, which dephosphorylates Lck's inhibitory tyrosine residue (Y505) to promote its activation, while CD45 can conversely dephosphorylate the activating Y394 site under certain conditions. Additionally, Lck engages ZAP-70 through its , binding to phosphorylated tyrosines such as Y319 on ZAP-70 to enhance signal propagation in the TCR pathway. Adapter proteins play a central role in Lck-mediated signalosome assembly, with Lck's SH3 domain binding a proline-rich motif (PIPRSP) in LAT to scaffold the complex and enable ZAP-70 access for LAT phosphorylation. SLP-76 is recruited to this LAT-centered signalosome, further organizing downstream effectors. For inhibitory scaffolding, the membrane adaptor PAG recruits Csk via its SH2 domain, positioning Csk to phosphorylate Lck at Y505 and dampen activity upon TCR stimulation. Computational predictions from 2024, employing tools like AF2Complex to model Lck's SH3 and SH2 domains against immune-related proteins, have proposed novel interactors such as the palmitoyltransferase zDHHC18 (iScore 0.59) and the checkpoint receptor LAG3 (iScore 0.40), potentially expanding Lck's regulatory network. Lck further interacts with cytoskeletal components, associating with in an SH2-dependent manner upon TCR engagement to support T cell motility and organization. These binding partnerships have been experimentally validated through co-immunoprecipitation (co-IP) to detect stable complexes and to identify direct interactions, with quantitative assays confirming nanomolar-range affinities for core associations like CD4-Lck.

Phosphorylation Substrates

Lck, a member of the Src family of kinases, primarily phosphorylates residues within immunoreceptor -based activation motifs (ITAMs) of the CD3 complex in the (TCR). These ITAMs contain multiple residues flanked by acidic residues, such as (D) or (E), which facilitate Lck binding and phosphorylation, initiating TCR signaling. Among its key substrates, Lck directly phosphorylates ZAP-70 at tyrosines Y315 and Y319 located in the interdomain B region. at these sites relieves auto-inhibition of ZAP-70, promoting its full activation and amplifying downstream TCR signals by enabling recruitment and of additional effectors. Lck also phosphorylates the adaptor protein LAT at specific sites including Y191 and Y226, which serve as docking platforms for SH2 domain-containing proteins like and PLC-γ1, thereby coordinating the assembly of multi-protein signaling complexes essential for T cell activation. Additionally, Lck contributes to the of PLC-γ1 at Y783, a critical activating site that enhances its activity and subsequent calcium mobilization in T cells. The consensus phosphorylation motif preferred by Lck features acidic residues N-terminal to the , exemplified by patterns like E/D-X-Y, which aligns with the sequences in ITAMs and other , promoting efficient recognition and modification. Phosphoproteomic studies using in T cells reveal a temporal in Lck following TCR stimulation: early events target ITAM tyrosines on CD3 (within seconds), followed by intermediate phosphorylation of ZAP-70, and later modification of adaptor proteins like LAT (peaking at 2-5 minutes post-stimulation). This sequencing ensures ordered signal propagation, with SILAC-based analyses confirming increased of these sites in Lck-dependent contexts.

Role in Disease

Immunodeficiencies and Genetic Disorders

Mutations in the LCK gene, encoding the lymphocyte-specific protein Lck, cause rare forms of (SCID) or combined immunodeficiencies (CIDs) through autosomal recessive inheritance. These loss-of-function mutations disrupt (TCR) signaling, leading to profound T cell defects, recurrent severe infections, and in affected individuals. A seminal example is the homozygous L341P , which results in a weakly expressed Lck protein with abolished activity, failing to restore TCR signaling in deficient T cells. In mouse models, Lck knockout (Lck^{-/-}) demonstrates the critical role of Lck in T cell development, with a profound block at the double-negative to double-positive stage, resulting in thymic and severely reduced mature T cells. These mice exhibit minimal peripheral T cells and impaired immune responses, mirroring human deficiencies. Clinical reports from the first described human LCK defects, including a 2012 case of autosomal recessive LCK deficiency with immunodysregulation and a 2016 report of a homozygous causing with low + T cells and recurrent infections. To date, fewer than 10 patients have been reported worldwide, underscoring the rarity of LCK mutations, which account for less than 1% of SCID cases. Diagnosis typically involves flow cytometry revealing severe CD4+ T cell lymphopenia, reduced CD8+ T cells, and impaired proximal TCR signaling, such as diminished of residues in signaling molecules like ZAP-70 upon stimulation. Genetic sequencing confirms biallelic LCK variants, with functional assays assessing activity. Recent 2023-2024 studies have refined genotype-phenotype correlations, showing that complete loss-of-function mutations (e.g., or frameshift) lead to SCID-like phenotypes with absent T cell function, while partial defects (e.g., P440S missense) cause milder CIDs with residual signaling, skewed memory T cells, and intestinal inflammation.

Autoimmune Diseases and Inflammation

Lck hyperactivity contributes to the loss of T cell tolerance in autoimmune diseases by promoting excessive T cell activation and pro-inflammatory signaling. In (RA), aberrant Lck expression enhances T cell-mediated synovial inflammation, driving joint destruction through sustained activation of downstream pathways. Similarly, in , Lck overexpression in T cells exacerbates airway hyperresponsiveness and eosinophilic infiltration, linking it to Th2-dominated allergic responses. Inhibition of Lck signaling has shown promise in attenuating pathogenic T helper responses associated with . For instance, Lck blockade reduces Th2 cell differentiation and production in models of allergic airway , thereby restoring regulatory T cell (Treg) balance and alleviating symptoms. In and related conditions like , Lck inhibition diminishes Th17 responses, which are critical for chronic , by interrupting IL-17 and secretion without broadly suppressing adaptive immunity. Lck also plays a role in allergic disorders and (GVHD) through its influence on function. Recent studies highlight Lck's involvement in antigen-driven cytotoxic T lymphocyte activity, leading to tissue damage in GVHD by amplifying perforin/granzyme-mediated lysis of host s. In (T1D), polymorphisms such as the rs10914542 G in the LCK impair TCR/CD3 signaling, leading to T cell hyporesponsiveness that increases susceptibility to beta-cell . Mechanistically, Lck sustains activation in T cells, promoting transcription of pro-inflammatory cytokines like TNF-α and IL-6, which perpetuate autoimmune inflammation. This occurs through Lck-initiated TCR signaling pathways that activate the IKK complex, leading to degradation and nuclear translocation. Animal models using Lck transgenic mice, such as those overexpressing Lck in T cells, demonstrate accelerated production and lupus-like phenotypes, underscoring Lck's role in breaking .

Role in Malignancies

Dysregulation of Lck, particularly through gain-of-function mutations or overexpression, contributes to oncogenesis in T-cell malignancies. In (T-ALL) and other T-cell lymphomas, Lck acts as a proto-oncogene by enhancing aberrant TCR signaling, promoting uncontrolled proliferation and survival of malignant T cells. For example, activating mutations in the LCK gene have been identified in T-ALL patients, leading to constitutive activity and leukemogenic . Additionally, Lck overexpression correlates with poor in certain T-cell non-Hodgkin lymphomas, where it drives anti-apoptotic pathways and tumor progression.

Therapeutic Targeting

Small Molecule Inhibitors

Small molecule inhibitors of tyrosine-protein kinase Lck primarily target its kinase domain to disrupt T-cell signaling, with many designed as ATP-competitive agents that bind the conserved ATP-binding pocket. These inhibitors were initially developed for broader Src family kinases due to structural similarities, but efforts have focused on enhancing Lck selectivity to minimize off-target effects on related kinases like and . Dasatinib, a dual BCR-ABL/Lck approved for , potently inhibits Lck with an IC50 of approximately 0.5 nM by competing for the ATP-binding site, leading to blockade of downstream T-cell activation pathways. Similarly, saracatinib (AZD0530), a Src/Lck dual , exhibits high potency against Lck with IC50 values in the 2.7–11 nM range, binding reversibly to the active conformation and showing selectivity over Abl. These compounds exemplify early of Src-targeted inhibitors for Lck, leveraging shared catalytic features while achieving nanomolar . Allosteric modulators of Lck, which target non-ATP sites such as the SH2 or SH3 domains to alter conformation, represent an emerging class for improved selectivity. Unlike endogenous negative regulators like Csk that phosphorylate inhibitory sites, these synthetic allosteric agents aim to disrupt protein-protein interactions without fully ablating catalytic activity. Recent studies have highlighted off-target effects of Lck inhibitors on cellular transporters, such as 2022 findings demonstrating that inhibition of Lck/ novel activity reduces OATP1B3-mediated uptake of anions, potentially altering and contributing to toxicity profiles of broad-spectrum TKIs like . The development history of Lck inhibitors traces back to the late 1990s, with early inhibitors repurposed based on , followed by structure-based design enabled by Lck kinase domain crystal structures resolved in complex with ATP-competitive ligands around 1999. This approach facilitated optimization of selectivity, as seen in subsequent generations of pyrrolopyrimidine and scaffolds targeting Lck-specific residues in the ATP pocket.

Clinical and Research Applications

Lck modulation has shown promise in clinical and preclinical settings for treating (T-ALL) and autoimmune conditions. , a multi-kinase that targets Lck, reduces T-cell signaling by inhibiting Lck and activation, leading to anti-leukemic effects in a subset of T-ALL cases. In preclinical models and patient-derived samples, suppresses Lck-dependent pathways, demonstrating in Lck-activated T-ALL cells, though responses can be transient. For autoimmune diseases like , saracatinib, a including Lck, has exhibited efficacy in preclinical studies by inhibiting necroptosis and inflammatory responses in imiquimod-induced mouse models of psoriatic , reducing MLKL and expression such as IL-17 and IL-23. Emerging research highlights the therapeutic potential of Lck-related kinase inhibitors in neurodegeneration and (GVHD) prevention following transplants. Reviews from 2025 underscore the role of family kinases, including Lck, in neurodegenerative pathways such as phosphorylation and microglial activation in Alzheimer's and Parkinson's diseases, with inhibitors like AZD0530 (saracatinib) showing preclinical benefits in reducing amyloid-beta production and neuronal . In transplantation, Lck activation contributes to T-cell mediated GVHD, and inhibitors suppress acute GVHD by targeting Lck at Ser59, suggesting opportunities for direct Lck inhibitors to enhance prophylaxis while preserving graft-versus-tumor effects. Key challenges in translating Lck-targeted therapies include achieving selectivity over other Src family kinases and identifying reliable . High among Src kinases (70-90% identity) complicates inhibitor design, often leading to off-target effects that limit clinical utility. at Tyr394 (pY394) serves as a biomarker for Lck activation, with flow cytometry-based pY394-Lck levels predicting sensitivity in pediatric T-ALL, enabling patient stratification in trials. Future directions focus on advanced modalities like proteolysis-targeting chimeras (PROTACs) for Lck degradation and computational tools for interaction prediction in . PROTAC-based degraders, such as dasatinib-linked chimeras, induce rapid ubiquitination and proteasomal degradation of Lck in T-ALL models, outperforming inhibitors by achieving sustained suppression of Lck signaling and enhanced even in resistant cells. In , deep learning tools like AF2Complex have enabled high-throughput prediction of Lck protein-protein interactions with over 1,000 immune-related proteins, facilitating the identification of novel druggable interfaces for T-cell signaling modulation.