Kinases Phosphatases, Volume 4, Issue 2 (June 2026) – 4 articles

Plant–pathogen interactions are shaped by dynamic regulatory processes that control immune signaling. Among these, post-translational modifications (PTMs) play central roles in modulating protein activity, stability, and interaction networks. Increasing evidence indicates that Phytophthora effectors target PTM-dependent regulatory systems to suppress host immunity and promote infection. Here, we synthesize current knowledge on how Phytophthora virulence factors manipulate post-translational regulation through two mechanistically distinct strategies: (i) canonical mechanisms, involving direct enzymatic modification of host proteins or the recruitment of host PTM-modifying enzymes, and (ii) non-canonical mechanisms, in which effectors alter the activity, organization, or localization of PTM-associated regulatory systems without directly inducing covalent modification. These processes frequently involve protein–protein interactions and oligomerization-dependent regulation that reshape signaling complexes and enzymatic accessibility. By distinguishing effector-mediated PTM induction from regulatory interference, we provide a mechanistic framework for interpreting how diverse virulence strategies converge on the control of immune signaling pathways, including those governing reactive oxygen species production, transcriptional regulation, hormone signaling, and cell death. We further highlight current limitations in mechanistic understanding and emphasize the need for integrative approaches combining structural biology and proteomics to resolve how effectors reprogram host signaling systems. Full article

Pediatric gastrointestinal (GI) cancers are rare malignancies that differ fundamentally from their adult counterparts in molecular drivers, histology, and clinical behavior. While adult GI cancers are frequently driven by recurrent oncogenic mutations, pediatric tumors often exhibit pathway-level dysregulation involving developmental signaling networks. Among these, the RAS/MAPK pathway emerges as a central convergent axis integrating growth factor signaling, developmental programs, inflammatory cues, and post-translational regulatory mechanisms. Increasing evidence suggests that aberrant phosphorylation dynamics result from imbalanced kinase activation and phosphatase-mediated signal attenuation, which contribute to sustained MAPK signaling in pediatric GI malignancies, even in the absence of canonical RAS or RAF mutations. This review synthesizes current knowledge on RAS/MAPK signaling in pediatric GI cancers, emphasizing the role of kinase–phosphatase imbalance, signal duration, and regulatory failure in shaping oncogenic outcomes. We highlight how altered phosphorylation control may influence tumor differentiation, therapeutic responsiveness, and resistance mechanisms, and discuss emerging opportunities for targeting signaling dynamics rather than single genetic lesions. This signaling-centric framework provides a biologically grounded rationale for functional biomarker-driven precision therapy in pediatric GI malignancies. Full article

Chronic lymphocytic leukemia (CLL) exhibits marked clinical heterogeneity that is closely associated with genomic instability. Although cytogenetic abnormalities are widely used for risk stratification, they do not fully capture the biological complexity of the disease. Telomere dysfunction and alterations in DNA damage response pathways have been implicated in disease progression, but their relationship with cytogenetic risk in CLL remains incompletely characterized. In this study, peripheral blood mononuclear cells (PBMCs) from 48 CLL patients were analyzed. The analyzed PBMC fractions were enriched in leukemic B cells, with an estimated median tumor content above 85–90%. Cytogenetic profiles were obtained by conventional karyotyping following in vitro immunostimulation with DSP30 and interleukin-2 and classified according to ERIC and Döhner criteria. Telomere length was assessed by quantitative PCR, and CHEK1 and CHEK2 expression levels were quantified by RT–qPCR. Molecular parameters were compared across cytogenetic risk groups. Distinct molecular profiles were observed across cytogenetic categories. Favorable-risk CLL cases showed preserved telomere length, low CHEK1 expression, and maintained CHEK2 levels. Intermediate-risk cases, predominantly characterized by trisomy 12, exhibited moderate telomere shortening accompanied by increased CHEK1 expression and partial reduction of CHEK2. High-risk CLL cases, defined by del(11q), del(17p), or complex karyotypes, displayed pronounced telomere shortening, marked CHEK1 upregulation, and strong suppression of CHEK2. Telomere length was inversely correlated with cytogenetic risk (Spearman’s ρ = −0.68, p < 0.0001), and the CHEK1/CHEK2 expression ratio increased progressively with genomic complexity. These findings indicate that telomere length and CHEK1/CHEK2 expression patterns are closely associated with cytogenetic risk in CLL and may provide complementary biological information for risk stratification. Full article

Protein kinase inhibition can be achieved through various mechanisms, including blocking phosphorylation activity or disrupting regulatory interactions. While small molecule inhibitors have shown promise, their selectivity remains challenging due to the structural similarities among kinase catalytic sites. To design selective kinase inhibitors based on peptide terminal tail interactions with the activation segment, focusing on five kinases with different conformational states: GSK3, PAK4, TTN (OUT conformation) and PKB, FLT3 (IN conformation). Three-dimensional structures from RCSB PDB were optimized using MODELLER version 9.0. Peptide sequences were designed with PeptiDerive (Rosetta) and RosettaDesign version 3.5, followed by pharmacophore modeling based on key interaction residues. Virtual screening was then conducted with PyRx 0.8 and molecular docking with AutoDock Vina 1.1.2. Molecular dynamics simulations were performed using Desmond v6.6 (Schrödinger Suite 2016, Multisim v3.8.5.19) (100 ns, NPT ensemble, 300 K). Analysis of the five kinases revealed distinct interaction profiles with designed peptidomimetic compounds. Kinases displaying the IN conformation of the activation segment (PKB and FLT3) consistently showed superior stability and stronger interaction profiles compared to those in the OUT conformation. The designed compounds formed key hydrogen bonds and hydrophobic interactions with critical residues in the activation segment binding pocket. The most promising inhibitors demonstrated stability throughout the molecular dynamics simulations, with IN conformation kinases maintaining more consistent conformational profiles than their OUT conformation counterparts. Kinases with IN conformation of the activation segment demonstrated superior stability and interaction profiles compared to OUT conformations. These findings contribute to our understanding of selective kinase inhibition and provide a framework for developing novel inhibitors, particularly for PKB and FLT3. The implications of this study extend to rational drug design approaches that leverage natural regulatory mechanisms for therapeutic intervention, though further optimization is needed for GSK-3β, PAK4, and TTN to improve stability and binding affinity. Full article