Receptor Protein Tyrosine Phosphatases (RPTPs): Structure and Biological Roles in Cancer

Abstract

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.

1. Introduction

Protein tyrosine phosphorylation forms the hallmark of eukaryotic signaling and regulates cellular processes, including cell division and proliferation [1]. The human genome contains approximately 95 Protein Tyrosine Kinases (PTKs) that catalyze the transfer of phosphates from ATP molecules to target tyrosine residues in proteins [2]. Most are activated by tyrosine phosphorylation of their activation loop regions, achieved through autophosphorylation in either a cis or trans configuration [3]. These PTKs, and their target signaling proteins, are dephosphorylated at their phosphotyrosines by 107 Protein Tyrosine Phosphatases (PTPs) [4,5]. Understandably, mutations in both PTKs and PTPs are recognized as being linked to numerous human diseases, including cancer [6,7,8,9,10]. Like the PTKs, PTPs exist in both cytosolic (e.g., PTP1B, TC-PTP, MEG1/2, SHP1/2) and receptor-bound forms (e.g., PTPα, PTPγ, LAR, CD45, DEP1, GLEPP1) [11,12]. Although protein tyrosine kinases (PTKs) have been well investigated and their function as oncogenic drivers is well established, research on protein tyrosine phosphatases (PTPs) has lagged, primarily because they are assumed to operate at a constant basal activity and function as housekeeping enzymes [13,14].

Within the framework of mitotic signaling, the function of protein tyrosine phosphatases (PTPs) is complex, and the existing literature is ambiguous, primarily due to the heterogeneous nature of tyrosine phosphorylation. Some phosphorylations, such as those on the activation loops of protein tyrosine kinases (PTKs), are activating, whereas others, like the C-tail phosphorylations on Src-family kinases, are inhibitory [15,16]. A significant number of reported phosphorylations remain without associated biological roles [17]. Thus, the elimination of specific phosphorylations by protein tyrosine phosphatases (PTPs) classifies them as either tumor suppressors or tumor promoters, depending on the cellular context under study (Figure 1) [18]. This review focuses on the structure and biological roles of receptor-bound forms of PTPs, called Receptor Protein Tyrosine Phosphatases (RPTPs), and details their presently known role in various cancers.

This review advances prior work on RPTPs and the cancer tyrosine phosphatome in three key ways. First, we integrate structural and evolutionary perspectives on tandem D1/D2 domains, including D2A and D2B subclasses, with detailed analysis of conserved catalytic motifs, dimerization, oxidation, and proteolytic processing. Second, we systematically examine RPTP protein expression across ten cancer types using CPTAC/ICPC proteomic datasets, defining subfamily- and cancer-type–specific alterations that extend existing genetic and biochemical data. Third, we propose a functional continuum from predominantly tumor-suppressive to context-dependent to oncogenic RPTPs and show how this framework can guide the design of RPTP-targeted therapeutic strategies. In contrast to many cancer-focused phosphatase reviews that emphasize non-receptor PTPs such as SHP2, PTP1B, and PTEN, our analysis centers on receptor PTPs, which remain comparatively underexplored despite their clear relevance to tumor biology and therapy.

2. The Conserved PTP Catalytic Domain and Mechanism

All RPTPs possess classical type-I cysteine-based PTP catalytic domains within their cytosolic regions. Certain RPTPs possess two PTP domains in tandem. A classical type-I conserved PTP domain has a globular structure consisting of twisted β-sheets surrounded by several α-helices (Figure 2a). The domain harbors ten conserved sequence motifs that define its structure and mechanism. These include four motifs at the PTP active site and another six structural motifs (Figure 2b) [11]. The structural motifs include Motifs-2–7 and form the stabilizing core of the PTP domain. Especially, residues from Motif-2 DxxR(V/I)xL, Motif-5 TxxDFWx(M/L/V)x(W)(E/Q), Motif-6 (I/L/V) (V/I)MxT and Motif-7 KCxxYWP form a hydrophobic cluster that affects the refolding properties and stability of the protein under temperature stress [19,20]. Motifs-3 DYINA(N/S) and Motif-4 (F/Y)IAxQGP form a parallel–antiparallel β-sheet at the core of the PTP domain. Cα-regiovariation score analysis reveals that the Motif-4 region surrounding the PTP active-site loop is the most conserved structural region of the PTP catalytic domain.

The active site motifs include Motif-1, Motif-8, Motif-9, and Motif-10. Motif-1 includes the sequence Nxx(K/R)NRY that possesses a conserved aromatic residue that recognizes the incoming phosphotyrosines by making π-π stacking interactions [21]. This motif sits in a loop called the pY-loop. Motif-8 includes the sequence (Y/F)xxWPDxGxP and is called the WPD loop, indicating the central residues. This region contains the general acid/base aspartate required for the catalytic reaction. Dynamics of the WPD-loop, which switches between open and closed conformations during the catalytic cycle, form the major determinants of the rate of the reaction at the PTP active site (Figure 2c) [22]. PTP activity is severely affected by mutations that alter the flexibility of the WPD-loop [23,24]. Motif-9 includes the sequence VHCSXGXGR(T/S)G and contains the CX₅R sequence and catalytic cysteine that define the classical type I PTPs. The active site cysteine covalently binds the incoming phosphate; hence, this loop is called the phosphate-binding or P-loop. Motif-10 has the sequence (V/I/L)QTxxQYxF, which includes the two conserved glutamines that activate water molecules at the PTP active site and is called the Q-loop.

Catalysis begins by recruitment of the phosphotyrosine-containing peptide at the active site cleft by the aromatic residue of the pY-loop. At this point, the WPD-loop closes, and a phenylalanine located downstream of the aspartate in the WPD loop positions the substrate deeper into the active site by allowing it to engage with the active-site cysteine. The catalytic reaction at the PTP active site proceeds via a two-step double-displacement mechanism (Figure 3) [25,26]. Step I: The active-site cysteine in the CX₅R sequence acts as a nucleophile and attacks the phosphorus of the phosphate group of the phosphotyrosine substrate. Simultaneously, the aspartate of the WPD-loop acts as a general acid and protonates the leaving product tyrosine. At the end of this step, the active-site cysteine is covalently bound to the substrate phosphate, forming a cysteinyl–phosphate intermediate. This reaction mechanism is hence also called covalent catalysis. The invariant arginine from the P-loop of the CX₅R motif interacts with the substrate’s phosphate group, facilitating the stabilization of the cysteinyl–phosphate intermediate. Step II: In the rate-limiting step of the reaction, a water molecule is activated by the glutamines of the Q-loop and is attacked by the deprotonated aspartate of the WPD loop that functions now as the general base [27]. As the cysteinyl–phosphate intermediate is hydrolyzed, inorganic phosphate is released in the cellular milieu, and the deprotonated active site cysteine is regenerated for the next round of catalysis.

3. Classification of RPTPs Based on Their Extracellular Domains

At the highest level, PTPs are classified into two types: membrane-bound receptor protein tyrosine phosphatases (RPTPs) and cytosolic non-receptor protein tyrosine phosphatases. These broad groups have been further differentiated into eight unique receptor PTPs and nine non-receptor PTPs using sequence ontology-based categorization approaches [5]. This sequence-based classification approach marks a substantial improvement over earlier methods. Previous classification schemes for receptor protein tyrosine phosphatases were based mostly on structural studies of their extracellular domains, yielding nine different categories [28]. However, using a sequence-based taxonomy focused on functional PTP catalytic domains has led to a more accurate reclassification approach. The revised approach has resulted in important reclassifications, including the chicken PTPλ, which was previously classified as a solitary member of the R6 subtype. Due to its significant sequence similarity with CD45, it has now been classified as a composite R1/R6 [5,10].

One particularly noteworthy characteristic of this classification method is that many receptor protein tyrosine phosphatase groups also include non-receptor protein tyrosine phosphatases due to the remarkable sequence similarity of their catalytic PTP domains (Figure 4). For example, the R7 subtype includes the cytoplasmic enzymes STEP and HePTP. Similarly, the R3 subtype includes both transmembrane and cytosolic isoforms of GLEPP1 (mouse PTPϕ) [29], while the R4 subtype includes both transmembrane and cytosolic isoforms of PTPε [30]. Furthermore, this phylogenetic analysis demonstrates that receptor protein tyrosine phosphatases with two tandem PTP catalytic domains form different clusters from those with only one catalytic PTP domain. This clustering pattern identified a PTP ‘supertype’ comprising the classes R1/R6, R2A, R2B, R4, and R5. Notably, the D1 domains in this supertype have significantly higher sequence identity (60–80%) than R3 PTP domains (45–60%). Furthermore, the supertype’s D2 domains constitute a separate branch in the evolutionary tree [10].

4. Two Catalytic Domains Containing RPTPs

The supertype of RPTPs with two PTP catalytic domains in their cytosolic regions includes the proteins: LAR, CD45, PTPα, PTPγ, PTPδ, PTPκ, PTPμ, PTPε, PTPσ, PTPζ, PTPρ and PTPλ. In all cases, the membrane proximal PTP domains (called D1) form an active phosphatase while the membrane distal PTP domain (called D2) is inactive (pseudo-phosphatase) (Figure 5) [18,31]. The only exception is PTPλ, whose tandem PTP domains are pseudo-enzymes [32]. Phylogenetic analysis of the D1 and D2 domains of these RPTPs indicates that both domains may have evolved from the same ancestral PTP domain [5,12,18]. For example, sequence similarity between the two LAR domains, PTPσ and PTPδ, is higher (ca 75%) than between the corresponding D1 domains (ca 45%) alone [33]. It is hypothesized that the D1 and D2 domains evolved independently following gene duplication, with the D2 domain acquiring mutations likely suited to its cryptic physiological role.

In the tandem PTP-domain RPTPs, the relative orientation of the D1 and D2 domains is remarkably conserved despite sequence differences. This conserved orientation is shown for CD45 in Figure 5. In these RPTPs, the D1 active site and D2 pseudo-active site are positioned roughly 90° apart and about 40 Å distant, connected by a short linker of ~12 residues that typically contains a conserved G[D/E]TE motif [31]. A dense interdomain interface including hydrogen bonds between D1 β-strands/α3 and the D2 β2–β3 loop, complementary surfaces between D1 α3/α6 and D2 α4/α5, hydrophobic contacts, and salt bridges such as Arg811/Arg812 (D1) with Glu1167/Asp1171 (D2) in CD45, stabilizes this arrangement. The short, relatively rigid linker and extensive interdomain contacts limit conformational freedom at the D1-D2 interface. Perturbing the linker or charged interfacial residues has been reported to disrupt D1–D2 communication and alter D1 catalytic activity, underscoring the functional importance of this conserved tandem-domain architecture [18].

The D2 domains can be further classified into two subclasses based on the positions of the mutations described above [34]. The D2A subclass includes LAR, PTPα, and PTPσ, whose D2 domains have a well-formed active site that differs from their corresponding D1 domains by only two residue substitutions. One is the substitution of the aromatic residue of the Motif-1 Nxx(K/R)NRY to an aliphatic Nxx(K/R)NR(V/L), and the second is the substitution of the Motif-8 (Y/F)xxWPDxGxP aspartate to a glutamate (Y/F)xxWPExGxP. The first substitution inactivates these D2 domains by reducing their catalytic efficiency by 60-fold and increasing the t_1/2 of phosphate hydrolysis by threefold [21]. The second substitution reduced the ability of the WPD-loop to close over the PTP active site as the substituted glutamate makes debilitating interactions with a nearby methionine [35]. Interestingly, reversing these two-point substitutions to the canonical sequences is reported to restore phosphatase activity in the D2A domains [35,36,37]. The D2B subclass includes CD45, PTPγ, PTPκ, PTPμ, PTPζ, PTPρ, and PTPλ. In contrast to the D2A domains, the D2B domains accumulate several substitutions at the entrance, around, and the backside of their active sites, which distorts their chemistry required to bind phosphotyrosines and perform a dephosphorylation reaction. These mutations vary among RPTPs and indicate that the D2B domains diverged from the D1 domains after their initial duplication. For example, in PTPγ and PTPζ, the D2 domain active site cysteine is substituted by an aspartate and in CD45 the residues around the active site of its D2 domain distort its phosphate-binding P-loop to make it inactive [38].

5. RPTP Catalytic Specificity and Regulation Mechanisms

The substrate selectivity of RPTPs is determined by the residues surrounding the catalytic pocket, the loop regions that interact with substrate proteins, and structural features that influence access to phosphotyrosine residues [21,39]. RPTP substrate recognition shows significant variation: many phosphatases exhibit broad substrate specificity, whereas others prefer highly selective substrates. This specificity is achieved through multiple processes, including spatial localization within cells, temporal expression patterns, the formation of signaling complexes that position enzymes and substrates in proximity, and the identification of sequence motifs adjacent to the phosphotyrosine residue. For example, CD45 (PTPRC) selectively dephosphorylates the inhibitory C-terminal tyrosine of Src family kinases, facilitating their activation, whereas PTPσ acts on specific substrates related to neurite outgrowth and axon guidance [40,41].

A fundamental regulation mechanism for RPTP activity encompasses dimerization and higher-order oligomerization [31,42]. Ligand binding to the extracellular domain may induce conformational changes that either facilitate or inhibit dimerization, thereby influencing phosphatase activity. The interaction of heparan sulfate proteoglycans with PTPσ facilitates oligomerization and diminishes catalytic activity, but ligand-induced dissociation of dimers can activate the phosphatase [43]. This process establishes a direct link between extracellular signals and intracellular phosphatase activity, enabling RPTPs to function as authentic receptors that transmit extracellular information across the plasma membrane. Investigations of the crystal structures of the intracellular catalytic domains and biochemical assays indicate that RPTP dimerization generally suppresses catalytic activity through structural rearrangements that obstruct the active site or hinder substrate access [42]. The “wedge model” posits that, during dimerization, a wedge-shaped helix-turn-helix motif from one protomer blocks the catalytic cleft of the neighboring protomer, thereby sterically obstructing substrate binding [44].

RPTPs are particularly susceptible to oxidative modulation due to the reactive cysteine residue in their active sites [45]. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) can oxidize the catalytic cysteine to form sulfenic acid, sulfinic acid, or sulfonic acid derivatives, resulting in either reversible or irreversible deactivation [45]. This oxidative process serves as a crucial physiological regulatory mechanism in growth factor signaling, wherein localized ROS generation coincides with receptor tyrosine kinase activation and transiently inactivates adjacent PTPs, thereby facilitating prolonged tyrosine phosphorylation. The reversibility of oxidative alterations is contingent upon the oxidation state: sulfenic acid can be reduced by cellular reducing agents, such as glutathione and thioredoxin, whereas sulfinic and sulfonic acid modifications are typically irreversible [46]. Certain RPTPs have developed defensive strategies against oxidative inactivation, such as conformational alterations that obscure the active site or the establishment of intramolecular disulfide bonds [31,45].

6. RPTPs and Their Signaling Effectors in Cancer

RPTPs play either oncogenic or tumor-suppressive roles through molecular interactions with specific effector proteins via direct physical binding, catalysis, or indirect regulatory networks (Figure 1). The extensive diversity of these interactions highlights the intricate, context-dependent functions that RPTPs perform in cancer biology. Detailing these molecular interactions is essential for understanding how RPTPs modulate cancer initiation, progression, and metastasis. Individual phosphatases frequently demonstrate opposing activities depending on cellular environment, substrate accessibility, and the interconnected signaling networks in which they operate. These context-dependent characteristics carry substantial implications for comprehending tumor biology and advancing targeted therapies.

6.1. PTPα and PTPε: Activators of SRC Family Kinases in Cellular Transformation and Adhesion

PTPα functions as a tumor promoter by directly activating SRC family kinases, including both SRC and FYN [47,48,49], while also directly interacting with focal adhesion kinase (FAK) [50,51,52]. The underlying molecular mechanism involves the catalytic removal of the inhibitory phosphate group from the C-terminal tyrosine residue (Y527 in human SRC) on SRC family kinases [53,54]. Hence, PTPα drives cellular transformation by sustaining SRC kinases in a persistently active conformation that bypasses regulatory mechanisms and enables these kinases to remain in catalytically competent conformations capable of phosphorylating diverse downstream substrates. In breast epidermoid carcinoma cells, PTPα-mediated SRC activation has been reported to trigger subsequent FAK activation and augment cellular adhesion to extracellular matrix components [55]. This enhanced adhesive capacity can paradoxically either suppress metastasis through stronger cellular anchorage or facilitate invasion by stabilizing the dynamic adhesion structures that enable cellular migration. The ultimate outcome in each tumor is determined by the cellular context and the additional signaling pathways operating within the cell.

Similarly, PTPε activates SRC directly and perpetuates the transformed phenotype of mammary tumor cells through sustained SRC activation [56]. The oncogenic capacity of PTPε-mediated SRC activation has been validated in experimental mammary carcinoma models where PTPε expression correlates with aggressive tumor characteristics and resistance to specific therapies. PTPε additionally activates the related kinases FYN and YES, though the precise contributions of these kinases to tumor cell biology remain less thoroughly characterized [57]. The overlapping yet distinguishable functions of PTPα and PTPε in SRC family kinase regulation underscore the sophisticated and redundant control of these crucial oncogenic kinases by distinct RPTP family members.

6.2. LAR: Context-Dependent Receptor Tyrosine Kinase Regulation and Complex Signaling Networks

LAR exhibits remarkably complex and paradoxical functions that depend on the specific substrate and cellular context. LAR directly activates SRC by dephosphorylating its inhibitory C-terminal tyrosine residue, and this activated SRC subsequently activates multiple components of the TRKB neurotrophin signaling pathway [58]. This, in turn, promotes cell-survival pathways, particularly in neuronal and neuroendocrine tumors, where neurotrophin signaling supports tumor cell viability. Similarly, in colorectal cancer, LAR is responsible for sustained Wnt/β-catenin signaling and supporting the growth of tumor organoids [59]. Conversely, LAR has been reported to directly suppress basal ABL kinase activity, thereby paradoxically maintaining PDGFR activity by eliminating ABL-mediated negative regulation of the receptor [60,61]. This intricate regulatory network demonstrates how a single RPTP can simultaneously activate and suppress disparate signaling pathways, with the net outcome determined by the balance of these opposing effects and the relative expression levels of the proteins involved in these pathways. LAR also broadly suppresses phosphatidylinositol 3-kinase (PI3-K) activation downstream of several key receptor tyrosine kinases, including insulin-like growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), and hepatocyte growth factor receptor (HGFR/MET), positioning it as a critical negative regulator of this essential survival pathway [62,63,64]. Given the frequent hyperactivation of PI3-K/AKT signaling in human cancers and its importance in promoting cell survival, metabolic reprogramming, and therapeutic resistance, LAR’s tumor-suppressive function through this mechanism is particularly significant. Loss of LAR expression, which occurs in various cancers through promoter hypermethylation or chromosomal deletion, is therefore expected to enhance PI3-K signaling and contribute to a malignant phenotype.

6.3. PTPρ and PTPζ: Cell Migration Control and Ligand-Dependent Regulation

PTPρ dephosphorylates paxillin (on Y88), a key component of focal adhesions that links integrins to the actin cytoskeleton and recruits numerous signaling molecules to sites of cell–matrix contact [65]. Through this interaction, PTPρ regulates both cell migration and anchorage-independent growth in cancer cells. Loss of PTPρ promotes metastatic behavior by dysregulating focal adhesion dynamics and enabling cells to proliferate in the absence of proper matrix attachment.

PTPζ represents a unique RPTP that responds to extracellular ligands, including pleiotrophin and midkine, both of which are upregulated in various cancers to promote tumor progression [66,67]. When pleiotrophin binds to the PTPζ extracellular domain, it suppresses its phosphatase activity through receptor dimerization or conformational changes that occlude the active site, thereby promoting tyrosine phosphorylation and activation of Wnt/β-catenin signaling [68,69]. Pleiotrophin binding has also been reported to increase phosphorylation of PTPζ-associated proteins, including β-adducin and FYN kinase [67,70]. PTPζ may also interact with calmodulin, suggesting calcium-dependent regulatory complexity that could integrate diverse signaling inputs and couple PTPζ activity to cellular calcium dynamics [71].

6.4. PTPδ, and PTPσ: Diverse Regulatory Functions Across Cancer Types

PTPδ is reported to directly or indirectly regulate STAT3 transcription factor activity, thereby suppressing glioma cell proliferation [72,73,74]. Given that STAT3 hyperactivation drives proliferation and survival in many gliomas and is activated by multiple receptor tyrosine kinases and cytokine receptors in the tumor microenvironment, PTPδ loss would be expected to promote tumor growth. This is consistent with its proposed tumor-suppressor function in brain cancers, in which PTPδ expression is frequently attenuated. In hepatocellular carcinoma, PTPδ is reported to dephosphorylate STAT3 at Y705 and prevent its nuclear translocation, thereby downregulating MMP-2 and MMP-9, resulting in the inhibition of proliferation and angiogenesis of tumor cells [75]. Also, PTPδ negatively regulates CXCL8, a chemokine secreted by tumor cells, thereby suppressing angiogenesis [76].

PTPσ dephosphorylates and directly suppresses EGFR signaling and causes inactivation of the PI3-K pathway required for mesenchymal progression of cancer cells [77,78]. PTPσ negatively regulates ERK activity and attenuates RAS signaling, which is required for tumor cell growth and angiogenesis [79]. The loss of PTPσ in various cancers through promoter methylation or deletion has been reported to enhance growth factor signaling and promote malignant properties, including uncontrolled proliferation and resistance to apoptosis [78].

6.5. DEP-1: A Multifunctional Phosphatase with a Diverse Substrate Repertoire

DEP-1 is among the most extensively characterized tumor-suppressive RPTPs, though its function is highly context-dependent across cancer types. DEP-1 executes its tumor-suppressive functions through multiple direct effector interactions that constrain oncogenic signaling. In breast cancer cells, DEP-1 negatively regulates MET receptor tyrosine kinase, the adaptor protein GAB-1, and the adherens junction protein p120-catenin [80,81]. DEP-1 exhibits exceptional substrate specificity by targeting highly specific tyrosine residues rather than causing indiscriminate dephosphorylation, enabling precise regulation of signaling outcomes. In gastric cancer, DEP-1 inhibits malignant transformation by dephosphorylating EGFR at Y1173, Y1068, and Y1092 sites and suppressing the MEK/ERK and PI3K/AKT pathways [82]. DEP-1 also directly inactivates PDGFR signaling through selective dephosphorylation while simultaneously preserving paxillin phosphorylation and normal cell adhesion [83]. However, DEP-1 can also exhibit context-dependent oncogenic functions. Phosphorylated DEP-1 binds to the SH2 domain of SRC, leading to dephosphorylation of SRC at the inhibitory Y529 residue and subsequent phosphorylation at the activating Y418 residue [84]. This DEP-1-mediated activation of SRC promotes tumor-associated angiogenesis, underscoring the complex and paradoxical roles of this phosphatase.

6.6. Nuclear and Membrane-Bound Forms of PTPκ and PTPμ: Dual Localization and Function

Several RPTPs, including PTPκ, PTPμ, and LAR, can exist as both full-length membrane-bound receptors and proteolytically cleaved nuclear forms, with these forms exhibiting distinct functions [18,85,86]. The nuclear forms directly bind to β-catenin, the key effector of canonical Wnt signaling, thereby altering transcription of key genes controlling cell proliferation, differentiation, and epithelial–mesenchymal transition. Evidence suggests that proteolytically cleaved RPTP fragments preferentially accumulate in the nucleus and bind to β-catenin with higher affinity than full-length receptors, indicating that proteolytic processing represents a sophisticated regulatory mechanism that redirects RPTP function from membrane signaling to nuclear transcriptional control. The proteases responsible for this cleavage and the signals that regulate it remain unknown and require further investigation.

PTPκ is reported to directly bind β-catenin and negatively regulates β-catenin-dependent transcription in the nucleus of melanoma cells, suppressing expression of cyclin D1 and other proliferative genes while inhibiting cell motility and invasion [87]. This tumor-suppressive function is antagonized in lung cancer cells, where lysyl oxidase-like protein (LOX-PP) induces proteolytic degradation of nuclear PTP [88]. This eliminates its ability to suppress β-catenin signaling and thereby promotes tumor progression through enhanced Wnt pathway, supporting proliferation, survival, and metastasis.

PTPμ directly interacts with the scaffolding protein RACK1 (Receptor for Activated C-Kinase 1), and through this interaction indirectly suppresses protein kinase C (PKC) activity by sequestering RACK1 away from PKC [89]. PKC suppression promotes cadherin-based cell–cell adhesion and maintains epithelial organization to inhibit epithelial–mesenchymal transition in metastatic cancer. Loss of PTPμ would therefore be expected to enhance PKC activity and disrupt epithelial integrity.

7. RPTP Expression and Signaling in Human Cancers: Analysis of CPTAC/ICPC Database

To systematically evaluate alterations in RPTP expression across human malignancies, we analyzed protein expression data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the International Cancer Proteogenome Consortium (ICPC) datasets, accessed through the UALCAN web portal [90,91]. We examined expression levels for multiple RPTPs across ten cancer types, including breast cancer, colon cancer, ovarian cancer, clear cell renal cell carcinoma (RCC), uterine corpus endometrial carcinoma (UCEC), lung cancer, pancreatic adenocarcinoma (PAAD), head and neck cancer, glioblastoma, and liver cancer. For each cancer type, tumor samples were compared with matched normal tissue controls across all samples to enable cross-cancer comparisons. Sample sizes varied by cancer type and are indicated for each comparison in the figures. UALCAN provides log2-normalized spectral count ratios that are further converted to Z-values (standard deviations from the median across samples) and displayed as box plots comparing normal and tumor tissues for each cancer type. In this review, we use these distributions qualitatively to highlight consistent shifts in expression between normal and tumor samples; we did not re-analyze the raw CPTAC data and therefore do not report formal p-values for these comparisons.

This comprehensive analysis of RPTP expression across multiple cancer types reveals several overarching themes. First, individual RPTPs can be classified along a spectrum from predominantly tumor-suppressive (PTPσ, PTPμ, DEP-1, PTPδ) to context-dependent (LAR, PTPκ) to potentially oncogenic (PTPα, PTPε). These classifications are not absolute and can vary with tissue type and the broader signaling network. Second, the magnitude and consistency of expression changes vary substantially among RPTPs, with some showing dramatic and uniform alterations (PTPμ, PTPσ) while others display more subtle or variable patterns (LAR, PTPκ). Third, expression-level changes represent only one mechanism of RPTP functional alteration; post-translational modifications, proteolytic processing, altered localization, and disrupted protein–protein interactions can all modulate RPTP activity without changing total protein abundance. Finally, the observed data emphasizes that RPTP functions are deeply embedded within tissue-specific signaling architectures.

The CPTAC/ICPC data confirm several RPTPs as predominantly tumor suppressors, including DEP-1, PTPδ, PTPσ, PTPρ, and PTPκ [92]. Among these, PTPσ exhibits the most uniform pattern across all cancer types examined, showing consistently elevated expression in normal tissue with marked downregulation in tumor samples (Figure 7). The striking uniformity of PTP downregulation across diverse malignancies spanning epithelial, mesenchymal, and neural lineages suggests that its inhibitory function on receptor tyrosine kinases provides a fundamental selective advantage during tumorigenesis, regardless of tissue origin. Notably, the tumor samples for PTPσ show limited sample sizes (n = 18 across all cancer types), yet the consistency of the pattern strengthens confidence in this observation. Moreover, the biological significance of PTP loss extends beyond simple removal of growth inhibition; PTP acts as a multifunctional barrier to both proliferation and metastatic dissemination through its regulation of EGFR signaling and its role in preventing EMT, making its inactivation a particularly critical event in cancer progression [77,79].

PTPκ shows comparable expression between normal and tumor samples across most cancer types, with a notable elevation in glioblastoma normal tissue (Figure 6). Despite this apparent preservation at the expression level, the discordance between relatively maintained expression and known tumor suppressor function suggests that PTPκ inactivation in many cancers may occur through post-translational mechanisms rather than transcriptional downregulation [4,87,88]. This highlights an important limitation of expression-level analysis: RPTPs can be functionally inactivated through mechanisms including oxidative modification of the catalytic cysteine, altered subcellular localization, proteolytic processing, or disruption of interactions with regulatory binding partners, none of which would be detected by measuring total protein abundance.

PTPμ demonstrates the most dramatic and consistent downregulation pattern among R2B subfamily members across nearly all cancer types examined. It is particularly reduced in breast cancer, where normal tissue expression is markedly elevated (Figure 6). The predominant pattern of PTPμ downregulation across diverse cancers suggests that in most tissue contexts, its adhesive functions are critical barriers to tumor progression [28,89]. The consistency and magnitude of PTPμ downregulation rival those of PTPσ, establishing both as among the most frequently inactivated RPTPs across human cancers. The near-universal nature of PTPμ loss suggests it may serve as a common checkpoint that must be overcome during malignant transformation across diverse tissue types.

CD45 (PTPRC), the sole member of the R1/R6 subfamily, exhibits variable expression patterns, with notable downregulation in normal renal and head-and-neck tissues relative to tumors (Figure 6). As CD45 is expressed exclusively in hematopoietic cells, the expression patterns observed in the CPTAC/ICPC data likely reflect differences in immune cell infiltration between tumors and adjacent normal tissue rather than tumor cell-intrinsic CD45 expression [41]. Downregulation in some normal tissues relative to tumors may indicate increased immune infiltration in the tumor microenvironment. This highlights an important consideration when interpreting RPTP expression data: changes may reflect alterations in tissue cellular composition rather than changes in expression within individual cell types.

PTPλ, although catalytically atypical among RPTPs, shows elevated normal tissue expression, particularly pronounced in uterine and head and neck cancers (Figure 7). The variable expression patterns across cancer types suggest context-dependent functions. This may relate to PTP’s unique structural features and its ability to function via protein–protein interactions independently of phosphatase activity, thereby allowing it to scaffold signaling complexes whose composition and downstream effects vary with cellular context.

LAR (PTPRF) exhibits variable expression patterns across cancer types, with elevated expression in normal kidney tissue but relatively balanced or slightly tumor-elevated expression in other malignancies (Figure 7). This variability contrasts sharply with the uniform patterns observed for PTPσ and PTPμ, suggesting that LAR’s role in cancer is highly context-dependent [59,60,61,62,63]. The cancer-type-specific expression patterns likely reflect the balance among LAR’s multiple functions, which can promote survival in some contexts while suppressing proliferation in others.

The R4 subfamily members PTPα and PTPε represent examples of RPTPs that can function oncogenically through activation of Src family kinases [47,48,49,50,51,52,53,54,55,56,57]. The CPTAC/ICPC data show that both PTPα and PTPε are elevated in normal breast tissue compared to tumors (Figure 8). This at first appears contradictory to their oncogenic classification. However, this pattern likely reflects the essential role of Src signaling in normal mammary epithelium for integrin-mediated adhesion, proper tissue architecture, and regulated proliferation during development and lactation [55]. During malignant transformation, alterations in other pathway components may shift the balance such that Src activation promotes invasion rather than structured adhesion, even as overall RPTP expression levels decline. Alternatively, the reduction in tumor samples may reflect selection against extremely high levels of Src activation that could trigger senescence or apoptotic checkpoints, with tumors maintaining moderate expression sufficient for oncogenic effects. PTPε shows particularly pronounced downregulation in normal renal tissue (Figure 8), suggesting tissue-specific regulatory mechanisms in the kidney that are distinct from those in other organs.

PTPδ presents an intriguing expression pattern, with a dramatic elevation in clear cell RCC normal tissue, with Z-scores exceeding 5, while showing relatively balanced expression between normal and tumor samples in other cancer types (Figure 8). The striking tissue-specific elevation of PTPδ in normal kidney tissue suggests highly specialized functions in renal homeostasis that extend beyond its general role as a regulator of proliferation and angiogenesis. This observation raises important questions about whether the extraordinarily high PTPδ expression in normal kidney reflects unique signaling requirements in renal epithelium, perhaps related to the intense filtration and reabsorption activities that require precise regulation of cell survival and proliferation signals. The relative preservation of PTPδ expression in clear cell RCC tumors, despite this dramatic elevation in normal tissue, contrasts with the more typical pattern of tumor suppressor downregulation and may indicate that alternative oncogenic mechanisms can compensate for the maintenance of PTPδ expression in this cancer type.

PTPγ displays moderately elevated expression in normal tissue across multiple cancer types, with particularly prominent elevation in lung cancer (Figure 9). The moderate and variable expression changes observed for PTPγ across cancer types suggest that it may function as a modulator rather than a primary driver or suppressor of tumorigenesis, consistent with its context-dependent effects on cell adhesion [18].

DEP-1 is expressed at elevated levels in normal breast tissue (Figure 9), consistent with its well-characterized tumor suppressor function in this malignancy. DEP-1 is frequently altered in solid tumors through promoter hypermethylation or deletion, with its expression negatively regulated by microRNAs including miR-328 and miR-155 [81,84]. The reduced DEP-1 expression observed in breast tumors correlates with loss of critical regulatory checkpoints that normally constrain mitogenic receptor signaling through multiple receptor tyrosine kinases [82,83]. Interestingly, DEP-1 expression patterns vary more substantially across other cancer types than PTPσ, suggesting that, while DEP-1 functions as a tumor suppressor, its role may be more tissue-specific and reflects differences in the relative importance of its various substrate interactions across tissues.

8. Therapeutic Implications: Challenges and Opportunities

Based on genetic, biochemical, and cell-biological studies summarized in Section 6, individual RPTPs can be functionally categorized along a spectrum from predominantly tumor-suppressive (e.g., PTPσ, PTPμ, DEP-1, PTPδ) to context-dependent (e.g., LAR, PTPκ) to potentially oncogenic (e.g., PTPα, PTPε). We use CPTAC/ICPC protein expression data not to define these roles de novo but to test whether tumor-associated changes in abundance are consistent with prior functional assignments and to highlight tissue-specific patterns. Importantly, altered expression alone is not sufficient to infer tumor-suppressive or oncogenic function as expression changes may reflect shifts in tissue composition or be uncoupled from catalytic activity, which can be modulated by oxidation, proteolysis, or mislocalization. Functional classification of RPTPs in this review therefore rests primarily on mechanistic data, with expression patterns providing a complementary systems-level perspective.

The context-dependent and often paradoxical roles of RPTPs in cancer present both significant challenges and unique opportunities for therapeutic intervention. For tumor-suppressive RPTPs such as PTPσ, PTPμ, and DEP-1, the therapeutic goal would be to restore expression or activity. However, this faces substantial technical hurdles. Reactivating transcriptionally silenced genes through demethylating agents or histone deacetylase inhibitors lacks the specificity required for targeted therapy. On the other hand, enhancing phosphatase activity pharmacologically, rather than the more conventional strategy of inhibiting enzymes, requires the development of entirely new classes of small molecules. Approaches such as gene therapy, nanoparticle-mediated delivery of functional RPTP constructs, or restoration of microRNA suppressors (by reversing miR-328- and miR-155-mediated DEP-1 downregulation) may provide alternative strategies, though each has its distinct translational challenges.

For context-dependent RPTPs like LAR and DEP-1, therapeutic intervention requires careful consideration of the specific cancer type, the dominant signaling pathways active in that context, and the expected balance of pro-tumorigenic and anti-tumorigenic RPTP functions. DEP-1, for instance, suppresses EGFR, PDGFR, VEGFR, and MET signaling in most contexts but can activate SRC to promote angiogenesis when phosphorylated. Understanding these molecular switches, including post-translational modifications, binding partners, and changes in subcellular localization that tip the balance between tumor-suppressive and tumor-promoting activities, could enable context-specific therapeutic strategies. For example, preventing DEP-1 phosphorylation or disrupting its interaction with the SRC SH2 domain might preserve its tumor-suppressive RTK regulation while blocking its pro-angiogenic Src activation.

For the oncogenic R4 subfamily members, PTPα and PTPε, conventional phosphatase inhibitor approaches are more applicable. Small molecules targeting the PTP active site, allosteric inhibitors that lock the enzyme in inactive conformations, or peptide-based approaches that disrupt PTPα/PTPε interactions with SRC family kinases could provide therapeutic benefit. However, selectivity remains a critical challenge given the conserved nature of PTP catalytic domains across the superfamily. Structure-based drug design that leverages unique features of PTPα and PTPε active sites, or targets of substrate-recruitment surfaces rather than catalytic sites, may provide avenues for selective inhibition. Their less studied D2 domains could also be explored.

The identification of CD45 expression alterations as likely reflecting immune cell infiltration rather than tumor-intrinsic changes highlights an important therapeutic consideration. Modulating tumor-infiltrating immune cell populations through checkpoint inhibitors or adoptive cell therapy will indirectly affect RPTP-dependent signaling. Understanding how CD45 activity in tumor-infiltrating T cells impacts anti-tumor immunity through regulation of LCK activation and TCR signal strength could inform combination strategies that pair immune checkpoint blockade with agents that modulate RPTP activity in immune cells [93,94].

9. Conclusions

The comprehensive picture that emerges from structural, biochemical, cell biological, and systems-level analyses of RPTPs is one of remarkable sophistication and context sensitivity. Far from functioning as simple constitutive negative regulators of tyrosine phosphorylation, RPTPs serve as signal-integrating nodes that couple extracellular cues to precise modulation of intracellular phosphorylation networks. Their diverse extracellular architectures enable responses to ligands, cell–cell contacts, and extracellular matrix components. Their regulated dimerization provides a mechanism for activity control. Their exquisite substrate selectivity allows targeting of specific phosphotyrosines on specific proteins in specific signaling contexts. Their susceptibility to oxidation couples their activity to redox-state and growth-factor signaling dynamics. Their proteolytic processing can redirect function from membrane-associated catalytic activity to nuclear transcriptional regulation.

In cancer, this sophisticated regulatory network is frequently disrupted. Tumor-suppressive RPTPs like PTPσ and PTPμ are silenced to permit unchecked receptor tyrosine kinase signaling and epithelial–mesenchymal transition. Context-dependent RPTPs, such as LAR and DEP-1, are lost, mutated, or post-translationally modified in ways that tip the balance from tumor suppression to tumor promotion. Oncogenic RPTPs, such as PTPα and PTPε, can be maintained or activated to sustain SRC family kinase signaling, which promotes invasion and metastasis. The CPTAC/ICPC expression analysis presented here provides a systematic foundation for understanding these alterations across diverse cancer types, revealing both common themes (the near-universal loss of PTPσ and PTPμ) and tissue-specific patterns (PTPδ’s dramatic elevation in normal kidney, LAR’s context-dependent expression).

Moving forward, the field must embrace the complexity and context-dependence of RPTP function rather than seeking overly simplified models. Each RPTP operates within a specific signaling network architecture that determines whether its activity ultimately suppresses or promotes tumorigenesis in a given tissue. Therapeutic strategies must be tailored accordingly: restoration of tumor suppressors, inhibition of oncogenic family members, and context-specific modulation of dual-function RPTPs. Advanced technologies, including CRISPR-based genetic manipulation, optogenetic control, single-cell multi-omics, spatial transcriptomics and proteomics, and artificial intelligence-driven network analysis, will be essential tools for dissecting these complex relationships. Given the tissue-specific and context-dependent functions, it is unlikely that a single RPTP-directed agent would be appropriate for all patients within a given cancer type. Instead, RPTP-targeted therapies would need to follow a precision-medicine approach that combines cancer-type-specific signaling features with each patient’s RPTP expression, mutation/epigenetic status, and downstream pathway activity.

Ultimately, understanding RPTPs offers not only opportunities for targeted therapeutic intervention but also fundamental insights into how cells integrate multiple signals to make fate decisions. The field is transitioning from the genomic era, in which mutations and expression changes are cataloged, to the functional era, where the consequences of these alterations for signaling network dynamics are understood. In this transition, RPTPs will serve as paradigmatic examples of context-dependent signaling regulation. The challenge ahead is to harness this understanding to develop therapeutic interventions that restore normal signaling network dynamics in cancer cells, tipping the balance back toward growth suppression, proper differentiation, and apoptotic sensitivity. With continued investment in basic mechanistic studies, development of new tool compounds and therapeutic modalities, and rigorous clinical translation, RPTP-targeted therapies may join kinase inhibitors and immunotherapies as key components of precision oncology.