Kinases Phosphatases, Volume 4, Issue 1 (March 2026) – 7 articles

Receptor protein tyrosine phosphatases (RPTPs) are transmembrane enzymes that counterbalance protein tyrosine kinase activity by catalyzing the removal of phosphate groups from tyrosine residues on target proteins. Despite their critical roles in regulating cellular proliferation, adhesion, differentiation, and survival, RPTPs remain significantly understudied compared to their kinase counterparts. Contrary to early assumptions that PTPs function as constitutive housekeeping enzymes, emerging evidence demonstrates that RPTPs exhibit highly context-dependent roles in cancer, functioning as tumor suppressors or tumor promoters, or displaying dual activities depending on tissue type, cellular environment, and the specific signaling networks involved. This review provides a comprehensive analysis of RPTP structure, catalytic mechanisms, regulatory processes, and interactions with signaling effectors in cancer. Through a systematic examination of RPTP expression patterns across ten cancer types using Clinical Proteomic Tumor Analysis Consortium (CPTAC) and International Cancer Proteogenome Consortium (ICPC) datasets, we identify subfamily-specific and cancer-type-specific expression alterations that correlate with established functional classifications. PTPσ and PTPμ emerge as uniformly downregulated tumor suppressors across diverse malignancies, whereas PTPα and PTPε display oncogenic potential by activating Src family kinases. Context-dependent RPTPs, such as LAR and DEP-1, exhibit variable expression patterns that reflect their complex, multifaceted signaling roles. These findings establish RPTPs as critical regulators of cancer signaling with significant therapeutic potential while underscoring the need to understand tissue-specific signaling architectures when developing RPTP-targeted interventions. Full article

Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations that inactivate TSC1 or TSC2 genes. TSC1 or TSC2 mutations activate the mammalian target of rapamycin complex 1 (mTORC1) protein kinase pathway. Although many patients inherit a single copy of a mutant TSC gene, somatic mutations that cause loss of heterozygosity in inhibitory neuroprogenitor cells are hypothesized to be one cause of abnormal development. This may lead to cortical malformations or benign growths along the ventricular-subventricular zone (V-SVZ), cortex, olfactory tract, and olfactory bulbs (OB). This idea is supported by focal single-cell knockout experiments that induce CRE-mediated recombination following neonatal electroporation of conditional Tsc2 or Tsc1 mice. Loss of Tsc2 causes mTORC1 pathway activation and the formation of striatal hamartomas composed of ectopic clusters of abnormal cells and cytomegalic neurons, including within the OB. Neural phenotypes in this model can be partially rescued with Rapalink-1, a bisteric mTOR inhibitor, demonstrating the importance of mTOR in pathogenesis. We previously demonstrated that global V-SVZ neural stem cell (NSC) Tsc2 mutation induced by nestin-CRE-ER^T2 causes mTORC1 pathway activation, which is accompanied by transcriptional and translational errors. While we previously described cultured NSCs and OB granule cells from these mice, we did not thoroughly describe changes outside this region. Here, we provide evidence that removal of Tsc2 from neonatal V-SVZ NSCs causes subtle and rare brain malformations. This is exemplified by ectopic clusters of cytomegalic neurons and mTORC1 activation. This data supports that loss of Tsc2 in NSCs during neonatal development leads to heterotopic clusters in the adult brain. This model may be useful to study TSC, but the rarity and stochastic nature of lesions make the use challenging for identifying mechanisms and testing therapies. Full article

Kinases are signaling molecules that are central to all aspects of life. Consequently, their dysregulation is implicated in numerous diseases, making kinases one of the most successful family of drug targets. However, due to the conserved catalytic domain of kinases, these drugs are frequently not selective for a specific target, and selective inhibitors—‘chemical probes’—are therefore necessary to understand the role of specific proteins or isoforms. Through the SGC chemical probe program, selective kinase inhibitors have been made available, focusing on understudied kinases. Here, we discuss recent examples of this effort and showcase how selectivity for these probes has been achieved using different approaches. Full article

Oncogenic kinase pathways, including PI3K/AKT, RAS/ERK/MAPK and JAK/STAT, are central drivers of cancer cell proliferation, survival and metastatic potential. However, excessive activation of these pathways imposes intrinsic cellular stresses, such as oncogene-induced senescence, DNA damage responses and apoptosis. Recent evidence reveals that cancer cells mimic immunoregulatory programs to mitigate these stresses by ectopically expressing inhibitory receptors traditionally found on hematopoietic cells. These receptors recruit phosphatases such as DUSPs, SHP1, SHIP1 and PP2A, which directly counteract hyperactivated kinases. Acting as dynamic homeostatic buffers, these phosphatases attenuate oncogenic signaling intensity, maintaining a balance that permits continued proliferation while preventing the activation of fail-safe tumor-suppressive mechanisms. This mechanism appears particularly relevant in metastasizing cancer populations, where elevated co-expression of inhibitory receptors and phosphatases correlates with survival advantage and adaptation under selective pressures. Understanding the dual roles of phosphatases, not only as classical tumor suppressors but also as modulators of signaling homeostasis, provides insight into cancer cell adaptation to oncogenic stress. Targeting the phosphatase–inhibitory receptor axis may selectively destabilize this balance, exposing vulnerabilities in aggressive, resistant or metastatic cancer cells. This review highlights emerging evidence for the phosphatase-mediated buffering of oncogenic kinase signaling, the molecular mechanisms underlying inhibitory receptor engagement and the clinical implications for tumor progression and therapy resistance. Full article

Reversible protein phosphorylation is an important regulatory mechanism in cellular signalling and disease, regulated by the opposing actions of kinases and phosphatases. Modern computer methods predict kinase–substrate or phosphatase–substrate interactions in isolation and lack specificity for biological conditions, neglecting triadic regulation. We present SPINET-KSP, a multi-modal LLM–Graph foundation model engineered for the prediction of kinase–substrate–phosphatase (KSP) triads with contextual awareness. SPINET-KSP integrates high-confidence interactomes (SIGNOR, BioGRID, STRING), structural contacts obtained from AlphaFold3, ESM-3 sequence embeddings, and a 512-dimensional cell-state manifold with 1612 quantitative phosphoproteomic conditions. A heterogeneous KSP graph is examined utilising a cross-attention Graphormer with Reversible Triad Attention to mimic kinase–phosphatase antagonism. SPINET-KSP, pre-trained on 3.41 million validated phospho-sites utilising masked phosphorylation modelling and contrastive cell-state learning, achieves an AUROC of 0.852 for kinase-family classification (sensitivity 0.821, specificity 0.834, MCC 0.655) and a Pearson correlation coefficient of 0.712 for phospho-occupancy prediction. In distinct 2025 mass spectrometry datasets, it identifies 72% of acknowledged cancer-resistance triads within the top 10 rankings and uncovers 247 supplementary triads validated using orthogonal proteomics. SPINET-KSP is the first foundational model for simulating context-dependent reversible phosphorylation, enabling the targeting of dysregulated kinase-phosphatase pathways in diseases. Full article

Trypanosoma cruzi is the protozoan parasite responsible for Chagas disease, a neglected tropical disease caused by trypanosomatids. Its success as pathogen relies on remarkable metabolic adaptability, stress tolerance, and complex interactions with mammalian hosts. Among the proteins contributing to these processes, nucleoside diphosphate kinases (NDPKs) and arginine kinase (AK) have emerged as central enzymes for parasite metabolism. NDPKs, beyond their canonical role in nucleotide homeostasis, are implicated in DNA repair and oxidative stress responses and are also secreted enzymes. AK, on the other hand, serves as a unique energy-buffering system absent in mammals, supporting parasite growth and adaptation to oxidative and metabolic stresses, including modulation of host immunity. Both enzymes display distinct subcellular localizations all along the parasite and through the life cycle, linking them to multiple roles important for parasite biology and survival. Recent studies have highlighted the impact of interfering these enzymes with several compounds on the viability of the organisms, suggesting new avenues to explore them as drug targets. This review provides a general overview of NDPKs and AK in T. cruzi, aiming to underline their relevance to a broader context of trypanosomatids. Their study not only broadens our understanding of parasite biology but also opens perspectives for applied research, including therapeutic alternatives for Chagas and related diseases. Full article

CK2α and CK2α’, two paralogous members of the human kinome, are catalytic subunits of protein kinase CK2. Together with the regulatory subunit CK2β, they form heterotetrameric holoenzymes. CK2 is the subject of efforts to develop effective and selective inhibitors. For this, secondary binding sites remote from the canonical ATP/GTP cavity are critical. A crystallographic fragment screening with CK2α’ crystals and an established molecular fragment collection was performed to identify new ligands at known or novel sites. It resulted in fourteen CK2α’/fragment structures. Five fragments were found at the CK2β interface of CK2α’ and three fragments at the established αD pocket, which exhibits subtle differences between CK2α and CK2α’; comparative co-crystallisations with CK2α showed that one of them binds to the αD pocket of CK2α’ exclusively. No fragments bound at the substrate-binding region of CK2α’, but a CK2α’ structure with dp10, a decameric section of the substrate-competitive inhibitor heparin, and the indenoindole-type ATP-competitive inhibitor 4w was determined. A comparison with a published CK2α/dp10 structure revealed features consistent with reports about substrate specificity differences between the isoenzymes: dp10 binds to CK2α’ and CK2α with opposite strand orientations, and the local conformations of the isoenzymes in the helix αD region are significantly different. Full article