The numbers behind the review are sobering. Between 1990 and 2021, the global burden of chronic kidney disease driven by type 2 diabetes nearly doubled, reflecting an increase of roughly 80 to 90 percent. In the United States, annual all-cause healthcare costs for an insured patient with diabetic kidney disease climb from about 30,000 dollars in early stages to approximately 119,000 dollars as the disease advances. These figures capture more than economic strain; they reflect a disease whose cellular and molecular underpinnings remain only partially mapped, and whose progression is rarely reversible once structural injury takes hold. The authors of the review, Grace LeBleu and Fawaz G. Haj, contend that aberrant tyrosine phosphorylation—a reversible chemical switch that controls how cells respond to insulin, growth factors, and inflammatory cues—is a hallmark of diabetic kidney injury, and that the enzymes which remove these phosphate marks deserve far greater therapeutic attention.

Tyrosine phosphorylation is governed by a tug of war between two enzyme families: protein tyrosine kinases, which add phosphate groups to proteins, and protein tyrosine phosphatases, which remove them. While kinases have long been celebrated drug targets, phosphatases were for years dismissed as undruggable, largely because their catalytic pockets are highly conserved and positively charged, making selective inhibition difficult. The human genome encodes more than 100 phosphatase genes, of which 38 are classical phosphatases that specifically target phosphotyrosine residues—21 of the receptor-type and 17 of the non-receptor-type. The review systematically catalogs the evidence linking each of these 38 enzymes to diabetic kidney disease, ranging from directly established contributors to those implicated only indirectly or not at all.

Among the most firmly established is PTP1B, encoded by the PTPN1 gene. Discovered in the late 1980s and early 1990s as a negative regulator of insulin signaling, PTP1B dephosphorylates the insulin receptor and dampens downstream cascades. In podocytes—the specialized cells whose foot processes form the kidney’s filtration barrier—PTP1B knockdown stabilizes the cytoskeleton and preserves insulin signaling under high-glucose conditions. Recent work identified the cytoskeletal protein alpha-actinin-4 as a PTP1B substrate in insulin-stimulated podocytes, linking the enzyme directly to podocyte motility. In mouse models, global PTP1B deletion markedly attenuates glomerular injury and reduces albuminuria without major changes in blood glucose or pressure, while podocyte-specific deletion or pharmacological inhibition preserves podocyte architecture and blunts glomerular basement membrane thickening. Notably, PTP1B expression has been reported to be elevated in glomerular biopsies from patients with diabetic kidney disease, lending human relevance to the animal findings.

SHP2, the product of PTPN11, has emerged as another central player. In podocytes exposed to high glucose, SHP2 expression rises alongside increased endoplasmic reticulum stress, activation of the inflammatory transcription factor NF-κB, and heightened cell motility; silencing the enzyme prevents these changes. In diabetic mice, elevated SHP2 phosphorylation appears in macrophages, glomeruli, and podocytes, and podocyte-specific genetic deletion or pharmacological inhibition preserves renal function, lowering albuminuria and blood urea nitrogen. Immunohistochemical analysis of renal biopsies from patients with diabetic kidney disease reveals elevated phosphorylated SHP2 at a key activating site, and small-molecule inhibitors such as SHP099 and PHPS1 have shown renoprotective effects in rodent models of both type 1 and type 2 diabetes. SHP1, encoded by PTPN6, tells a similar story: hyperglycemia raises its expression in podocytes, disrupting insulin signaling and promoting apoptosis, while podocyte-specific deletion of SHP1 reduces albuminuria and reverses features of disease progression, apparently by restoring SUMOylation of the slit diaphragm protein podocin.

The review also spotlights endothelial and podocyte receptor-type phosphatases with distinctive renal roles. VEPTP, encoded by PTPRB, is largely restricted to endothelial cells in the adult kidney, where it dephosphorylates the angiopoietin receptor TIE2. Hyperglycemia, osmotic stress, and hypoxia all increase VEPTP expression, and inducible genetic deletion in diabetic mice improves glomerular filtration rate, reduces matrix accumulation, and preserves podocyte integrity—although an antibody-based inhibition approach alone failed to improve albuminuria, hinting that endothelial protection must be paired with therapies addressing the filtration barrier itself. CD148, encoded by PTPRJ, dephosphorylates growth factor receptors including VEGFR2 and EGFR, and an agonistic anti-CD148 antibody that boosts the enzyme’s activity attenuated albuminuria and mesangial expansion in diabetic mice. GLEPP1, encoded by PTPRO, sits on the apical surface of podocytes, and its deletion produces structurally abnormal foot processes, hypertension, and reduced filtration capacity, while its expression is diminished in sclerosed glomeruli from patients with diabetic kidney disease.

Beyond these established players, the review traces a broader web of phosphatases implicated in diabetes and renal pathology. TCPTP dephosphorylates the insulin receptor non-redundantly with PTP1B; its overexpression via gene therapy ameliorated albuminuria and renal morphology in diabetic mice, and its levels are reduced in patients with early-stage diabetic kidney disease. PEZ, or PTPN14, modulates the Hippo pathway through YAP and drives inflammatory and fibrotic signaling via TRIP6, with elevated expression detected in diabetic glomeruli and patient kidneys. RPTPζ serves as a receptor for interleukin-34, recruiting macrophages to injured tubules, while RPTPγ functions as a carbon dioxide and bicarbonate sensor in proximal tubular cells and rises in the serum as diabetic kidney disease progresses. Immune-associated phosphatases such as CD45, PTPN22, and HePTP connect renal inflammation and fibrosis to leukocyte signaling, and a cluster of enzymes including LAR, RPTPε, RPTPσ, and PTP-MEG2 modulate insulin signaling in muscle, liver, and adipose tissue, with several genetic variants linked to type 2 diabetes risk.

What makes the moment ripe for phosphatase-directed therapy is a confluence of pharmacological progress. Current standard care—RAAS blockade with ACE inhibitors or angiotensin receptor blockers, SGLT2 inhibitors validated by the DAPA-CKD, EMPA-KIDNEY, and CREDENCE trials, GLP-1 receptor agonists demonstrated in the FLOW trial, and the nonsteroidal mineralocorticoid receptor antagonist finerenone—slows disease but rarely reverses injury. Combination regimens are increasingly viewed as the path forward, and phosphatase modulators could slot into this framework as complementary agents. SHP2 inhibitors have already advanced through phase I, II, and III oncology trials, while the allosteric inhibitor SHP099 reduced albuminuria and blood urea nitrogen in diabetic mouse models. PTP1B inhibitors including ertiprotafib and trodusquemine reached clinical trials for type 2 diabetes and obesity, and an antisense oligonucleotide, IONIS-PTP-1BRx, lowered HbA1c and body weight in overweight patients with type 2 diabetes. VEPTP inhibition with AKB-9778 progressed to phase II trials for diabetic retinopathy, where patients showed a modest reduction in urinary albumin-to-creatinine ratio.

Novel modalities are expanding the toolbox further. Allosteric inhibitors that bind sites outside the conserved catalytic pocket promise improved selectivity, bivalent ligands engage both active and adjacent sites, and targeted protein degradation via PROTAC technology—exemplified by the SHP2 degrader SHP2-D26—offers a route to eliminate rather than merely inhibit the enzyme. Artificial intelligence and machine learning workflows have already been applied to PTP1B and SHP2 inhibitor discovery, helping overcome the historical barrier of conserved catalytic pockets by identifying selective binding modes and optimized physicochemical properties. The authors emphasize that pharmacological modulation need not mean inhibition in every case: for CD148, whose activity appears protective, an activation strategy is the goal, illustrating the nuanced directionality of phosphatase drug development.

The review’s bottom line is a call to translational action. Diabetic kidney disease remains the leading cause of end-stage renal failure, and existing therapies, however effective at slowing decline, rarely restore lost function. Classical protein tyrosine phosphatases sit upstream of the insulin, inflammatory, oxidative stress, and cytoskeletal cascades that converge to destroy the kidney in diabetes, and several are now pharmacologically tractable. The challenge ahead lies in bridging preclinical promise to clinical reality—defining cell-type-specific roles, establishing context-dependent effects in human disease, and testing phosphatase-targeted agents in combination with established therapies. If that bridge can be built, enzymes once written off as undruggable may finally deliver the precision treatments that patients with diabetic kidney disease have been waiting for.

Subject of Research: The roles of classical protein tyrosine phosphatases in the pathogenesis and treatment of diabetic kidney disease

Article Title: The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications

Article References: LeBleu, G., & Haj, F. G. (2026). The role of classical protein tyrosine phosphatases in diabetic kidney disease and therapeutic implications. Journal of Biomedical Science, 33(1), Article 89. https://doi.org/10.1186/s12929-026-01282-7

Image Credits: AI Generated

DOI: 10.1186/s12929-026-01282-7

Keywords: diabetic kidney disease, protein tyrosine phosphatases, PTP1B, SHP2, podocytes, insulin signaling, renal fibrosis, SGLT2 inhibitors, phosphatase inhibitors, drug discovery, chronic kidney disease, inflammation

One major challenge in fully understanding PTPs lies in the complexity of their regulation. Unlike PTKs, which primarily function to add phosphate groups to tyrosine residues on target proteins, PTPs reverse this process, removing phosphate groups and thereby modulating the activity of their substrates. This action has profound implications for cellular outcomes and necessitates stringent regulation. Recent studies have uncovered sophisticated mechanisms by which PTP activity is altered, including through post-translational modifications, protein-protein interactions, and changes in cellular localization, all of which fine-tune their functions in response to external signals.

The duality of action between PTKs and PTPs establishes a balance that is crucial for maintaining homeostasis within the cell. Dysregulation of either of these enzyme classes can lead to pathological states. In cancers, for example, aberrant tyrosine phosphorylation patterns have been linked to uncontrolled cell proliferation and survival. While PTKs driving oncogenesis have received considerable attention, PTPs that can serve as tumor suppressors or oncogenes warrant further investigation. Understanding which PTPs are altered in various cancers could not only shed light on tumor biology but also guide the development of new therapeutic approaches.

PTPs are not only significant players in cancer but are also intricately involved in metabolic diseases such as diabetes and obesity. Insulin signaling, for instance, is heavily regulated by PTPs, which can modulate pathways that control glucose metabolism. In insulin resistance scenarios, the activity of certain PTPs increases, leading to decreased insulin signaling and a downstream impact on glucose homeostasis. This link positions PTP inhibition as a promising strategy to restore insulin sensitivity and combat type 2 diabetes—a condition affecting millions globally.

In addition to cancer and metabolic disorders, PTPs have been implicated in neurodegenerative diseases, a largely overlooked area that may benefit from targeted PTP-based therapies. The role of PTPs in the central nervous system is multifaceted, influencing neuronal development, synaptic plasticity, and neuroinflammation. Pathologies like Alzheimer’s disease exhibit altered PTP activity, suggesting that restoring normal PTP function could have therapeutic implications in neurodegeneration.

The clinical investigation of PTP-targeting strategies is bolstered by the growing understanding of their mechanisms and their roles in various diseases. Early-stage research has led to the identification of small-molecule inhibitors that selectively target PTPs involved in disease progression. These inhibitors can block the phosphatase activity of specific PTPs, thus mimicking the effects of phosphorylation and enabling a therapeutic turnaround. Early trials are already underway, hinting at vast potential across a landscape that has remained largely untapped.

Moreover, the leap into the clinic for PTP-targeted therapies faces numerous challenges. One key hurdle lies in the heterogeneity of PTPs themselves, as there are more than 100 distinct PTPs encoded in the human genome, each with varying tissue distribution, substrate specificity, and regulatory mechanisms. The precision required to modulate specific PTPs without inadvertently affecting others necessitates advanced biochemical assays and animal models that faithfully replicate human disease contexts.

Furthermore, the potential for side effects associated with broad inhibition of PTPs must be addressed. The paradox of PTP inhibition—where enhanced signaling in one pathway could suppress another critical pathway—underlines the importance of understanding the broader signaling network in which these enzymes operate. Comprehensive systems biology approaches combining genomics, proteomics, and metabolomics will be crucial to unraveling these complexities.

The rise of precision medicine, coupled with deep-learning techniques and high-throughput screening, provides unprecedented avenues for discovering and optimizing PTP-targeting compounds. The challenge and opportunity lie in moving quickly from bench to bedside while gathering robust clinical data that elucidates how PTP modulation impacts disease outcomes.

Given the wealth of knowledge accumulated around PTPs in an array of pathophysiological contexts, we may be on the brink of a revolutionary shift in how diseases are treated—a shift that recognizes the exceptional potential of small molecules that can recalibrate the signaling landscape of our cells. As the understanding of PTP biology continues to expand, researchers and pharmaceutical companies alike are recognizing that these enzymes could represent a new frontier in drug development, broadening the arsenal available for tackling diseases that are currently poorly managed.

In conclusion, the intricate world of protein tyrosine phosphatases is on the cusp of a renaissance in therapeutic application. By illuminating the drivers of disease at the molecular level, PTPs are emerging from the shadows of their kinase counterparts. This evolution invites a clarion call for more investment into PTP-focused research. Emphasizing the therapeutic promise of PTPs could not only enhance our understanding of cellular mechanisms but also open new pathways for effective treatments, thereby positively impacting human health across a spectrum of conditions.

Subject of Research: Protein tyrosine phosphatases in cell signaling and disease.

Article Title: Mechanisms, functions and therapeutic targeting of protein tyrosine phosphatases.

Article References:

Tiganis, T., Tonks, N.K. Mechanisms, functions and therapeutic targeting of protein tyrosine phosphatases.
Nat Rev Mol Cell Biol (2025). https://doi.org/10.1038/s41580-025-00882-9

Image Credits: AI Generated

DOI:

Keywords: Protein tyrosine phosphatases, signaling, cancer, diabetes, therapeutics, drug development, precision medicine.