The activation of the RAS/ERK pathway is incomplete without the involvement of SHP2 (20). When stimulated by growth factors (such as epidermal growth factor [EGF], platelet-derived growth factors [PDGFs]), active receptor tyrosine kinases (RTKs, including epidermal growth factor receptor [EGFR], epidermal growth factor receptor type 2 [HER2], platelet-derived and fibroblast growth factor receptors [PDGFRs]) or active cytokine-receptors (such as interleukin 3 [IL-3], interleukin 6 [IL-6], and granulocyte macrophage-colony stimulating factor [GM-CSF]) attract SHP2 by exposing phosphorylated tyrosine residues. The C-terminal tyrosine residues of SHP2 may then be also phosphorylated as a mechanism of activation. However, this phosphorylation is not necessary for SHP2’s autoinhibited conformation to be relieved and for it to be ready for phosphatase action. In order to activate downstream effectors, SHP2 will ultimately dephosphorylate downstream signaling molecules. SHP2, however, may also function as a relatively low-dependence adapter protein, bringing proteins in close proximity for interaction, based on its SH2-domain characteristics.

For full activation of the RAS pathway, both of these molecular roles are important: SHP2 serves as an adapter protein by recruiting phosphotyrosine binding substrates like GRB2, insulin receptor substrate 1 (IRS1), fibroblast growth factor receptor substrate 2 (FRS2), Src homology, and collagen homology (Shc) to the membrane receptor tyrosine kinases in response to extracellular stimuli. GAB1/2, or GRB2-associated-binding proteins 1/2, are significant SHP2 binding partners. They have two SHP2 binding sites. These sites are first autophosphorylated to create a double-phosphorylated tyrosine activation motif during GAB1/2 activation. Subsequently, this motif binds to the two SH2 domains of SHP2, leading to the release and activation of the closed conformation within the SHP2 molecule. The Son of Sevenless (SOS) proteins aggregate at the cell membrane as a result of GRB2 binding to phosphorylated growth factor receptors or SHP2 binding to GRB2 via GAB1/2. The membrane-binding protein RAS can be catalyzed by SOS, a guanine nucleotide exchange factor (GEF), to transition from its inactive RAS-GDP state to the active RAS-GTP state. RAS-GTP then acts as a bridge to downstream signaling systems, triggering the activation of the RAF-1 serine/threonine kinase and amplifying the kinase cascade via MEK1/2 kinase, which in turn activates ERK1/2. Following activation, ERK1/2 regulates gene transcription by acting directly on cytoplasmic target molecules or translocates to the nucleus, which in the end promotes cell proliferation or differentiation (21, 22).

In order to transfer cascade activation signals, SHP2 may also indirectly bind to Sprouty (Spry), p120 RAS GTPase activating protein (p120 RAS GAP), and Src family kinase (SFK) in the RAS-RAF-MEK-ERK pathway (23–26). These scaffold proteins with their conserved tyrosine residues not only operate as adaptor proteins but also have the ability to quickly become dephosphorylated through interaction with SHP2, which sets off a series of stimuli signals. For example, in an inactivation/baseline state, mouse Sprouty2 (mSpry2) can form complexes with SHP2, GAP1 and GRB2, distant from the plasma membrane. Spry’s “trap effect” is caused by the binding between SHP2 and Spry2, which also keeps Spry dephosphorylated. Upon stimulation with e.g. fibroblast growth factor 10 (FGF10), phosphorylated Spry2 disengages from diverse complexes and relocates to the cell membrane. Subsequently, the adaptor protein FRS2 recruits the GRB2/SOS complex, facilitating the FGF10-induced MAPK cascade signaling (24, 27).

Via a positive signaling route, SHP2 can also facilitate EGF-induced RAS activation by dephosphorylating p120 RAS GAP (20). Thus, the half-life of RAS binding to GTP is significantly extended, prolonging RAS activation, since RAS-GAP, in this state, is unable to translocate to the plasma membrane for interaction with RAS (22).

Moreover, SRC and SHP2 dynamically regulate a tyrosine phosphorylation of KRAS at Tyr32 and Tyr64, contributing to the molecular switching role of RAS and influencing GEF-mediated nucleotide exchange (28, 29).

In addition, a recent study suggests that SHP2 interacts with the scaffold protein kinase suppressor of RAS1 (KSR1). This interaction results in the detachment of KSR1 from activated SHP2, followed by anchoring to the plasma membrane through the dephosphorylation of Tyr25, facilitating ERK signal transduction (30).

While the mechanistic roles of SHP2 in RAS-activation are manifold and context-dependent, a number of biochemical and genetic studies have now accumulated evidence that SHP2 is an important upstream regulator of even oncogenic mutant RAS isoforms (31, 32). Genetic knockout or pharmacological inhibition of SHP2 has the potential to inhibit full RAS/MAPK signaling thereby limiting progression of a range of tumors dependent on activated RTKs but also those with mutant RAS oncoproteins (6, 8, 33).

Activation of SHP2 downstream of growth factor receptors also governs the growth and survival signaling pathway of PI3K-AKT kinase (34, 35). PI3Ks, a family of lipid kinases, are essential for regulating diverse cellular processes such as development, proliferation, apoptosis, migration, and metabolism. Several upstream factors, such as RTKs or G-protein-coupled receptors, which cause PI3K recruitment to the membrane, can activate PI3K (36). As previously noted, receptor dimerization and autophosphorylation of tyrosine residues on receptor tyrosine kinases (RTKs) occur upon ligand binding. This process is followed by interactions with molecules that possess an SH2 domain (37). PI3Ks can be activated in three distinct manners (1): The activation of the catalytic subunit p110 of PI3Ks is triggered by the interaction of the regulatory subunit p85 of PI3Ks with phosphorylated motifs within RTKs (38) (2); It preferentially attaches to the phosphorylation motifs of RTKs as well as the scaffold protein GAB1/2 can subsequently bind to p85 (39) (3); RAS binding: GRB2 binds and activates SOS, thereby instigating RAS activation, which activates p110 autonomously from p85 (40).

PI3K regulatory subunit SH2 domain binding affinity can be directed toward phosphotyrosine residues of RTK or adaptor proteins, including IRS1, facilitating activation. This activation can occur both in an RTK-dependent and RAS-independent manner (41). PI3K’s upstream molecule IRS1 is in charge of attaching to and continuously activating PI3K, which in turn recruits downstream AKT (42, 43). Partially because of the connection between IRS-1 and SHP2, some PI3K binding motifs get dephosphorylated. Subsequently, protein synthesis is diminished, and the PI3K cascade signaling pathway is inhibited. Complete activation of AKT occurs through phosphorylation at the hydrophobic motif S473 in the carboxy terminus via the mammalian rapamycin complex 2 target (mTORC2) (44). After AKT is phosphorylated, several downstream targets crucial for controlling cell survival and death are also phosphorylated. By phosphorylating and deactivating a 40 kDa proline-rich AKT substrate (PRAS40) and tuberculosis 2 (TSC2), phosphorylated AKT stimulates the mammalian rapamycin target (mTOR) (45). Moreover, AKT prevents the phosphorylation of glycogen synthase kinase 3 (GSK-3), thereby stimulating the synthesis of cell cycle regulatory molecules like c-myc, cyclin D1, and cyclin E (46). Remarkably, AKT has the potential to activate the IκB kinase (IKK) and the NF-κB signaling pathway. To summarize, the IKK/NF-κB signaling pathway is implicated in multiple phases of cancer development and progression (47).

PI3K’s stimulation in reaction to growth factors via RAS involves a two-stage process. Phosphorylation of RTKs, which are occasionally adapter proteins, is the initial stage. Then RAS is activated in the second phase of the process. RAS-GTP interacts with PI3K p110α. Their direct contact increases the activity of p110α. This can be done by bringing substrate binding sites into a new conformation, boosting their catalytic activity, or facilitating tighter connections with the plasma membrane. RAS is primarily employed to stabilize PI3K on the plasma membrane, which is triggered by conformational changes in RTK, for RTK-induced mammalian PI3K activation (48). The activation of p110α results from the disruption of the inhibitory contact between SH2 and the catalytic subunit. This occurs when the ligand binds to the RTK, connecting the phosphorylated tyrosine motif in the receptor to the SH2 domain of p85 (49). The separation of p110 and p85 reduces the inhibition of p85 for Ras-mediated PI3K activation, and p85’s SH2 domain is essential (50). The PI3K catalytic subunit p110 is directly bound by the active RAS at amino acids that are distinct from those needed for p85 binding.

Determining whether a given stimulus activates PI3K through RAS-dependent, p85-independent, or RAS-independent processes is often challenging, as many stimuli activating PI3K also trigger activation of both p85 and RAS (51). As a result, SHP2 plays a variety of intricate roles in these processes, which can be redundant, stimulating, or inhibiting, depending on the situation.

Numerous pieces of evidence indicate that β-catenin stability is also influenced by tyrosine kinase activation. For instance, several tyrosine residues in EGFR, c-MET, and RON can be directly phosphorylated by active RTK, which increases transcriptional activity and protein stability for β-catenin. Furthermore, it has been reported that activated downstream signaling molecules, including AKT and ERK1/2, phosphorylate inhibitory Ser9 residues, leading to the inactivation of glycogen synthase kinase 3β (GSK-3β) and consequently stabilizing β-catenin (52). SHP2 serves as an upstream regulator in this signaling pathway. Given that RTK activation is the primary mechanism for initiating signal transduction via the RAS-RAF-MEK-ERK and PI3K-AKT pathways, SHP2 may mediate RTK induction, influencing the stability of β-catenin. In certain instances, SHP2-dependent β-catenin stability may be essential for tumor development, cell proliferation, transformation, and metastasis (53). Similarly, the β-catenin signaling pathway is implicated in the induction of epithelial-mesenchymal transition (EMT), possibly influenced by SHP2 (54).

It is noteworthy that parafibromin, a tumor inhibitor, recruits SUV39H1 histone methyltransferase to block cyclin D1 and c-myc (55). Nevertheless, β-catenin proteins that bind to parafibromin can also operate in the reverse way, triggering the pro-mitotic/carcinogenic Wnt signaling pathway (56). Only after tyrosine dephosphorylation by SHP2, parafibromin acquires stable binding β-catenin abilities. The parafibromin/β-catenin interaction then leads to an augmentation in the expression of Wnt target genes, including c-myc and cyclin D1 (57).

In governing how cells respond to extracellular cytokines, the JAK-STAT pathway is of vital importance. Seven STAT members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, as well as STAT6) and four JAK members (JAK1, JAK2, JAK3, and TYK2) have been found in mammalian cells. The several subtypes point to the JAK-STAT pathway’s functional complexity. JAKs belong to the non-receptor tyrosine kinase family. STAT proteins engage in the transcription and expression of a multitude of target genes within the nucleus concurrently. These mechanisms are essential for various cellular processes, encompassing immunological control, differentiation, cell survival, and inflammation. The primary downstream effector of cytokines, such as type I/II interferon and many interleukins, including IL-6 and IL-10, is the JAK-STAT pathway (58, 59). The current framework of the JAK-STAT signaling cascade posits that receptor oligomerization occurs when cytokines bind to their respective cell surface receptors; this oligomerization then activates JAK tyrosine kinases that are correlated with the receptor. By phosphorylating the tyrosine residues of the receptor, activated JAK creates binding sites for STAT recruitment and phosphorylation (60). Following dimerization, phosphorylated STATs dissociate from the receptor and translocate to the nucleus, initiating the transcription of genes (61).

Multiple strategies can be employed to modulate JAK-STAT signaling at different stages. The suppressor of cytokine signaling (SOCS) protein and the protein inhibitor of the activated STAT (PIAS) family, as well as diverse protein tyrosine phosphatases (PTPs) are important regulatory elements. SHP2 may either strengthen or weaken the JAK-STAT pathway according to substrate specificity, much like the two-edged sword in the PI3K-AKT signaling pathway (62).

On the one hand, SHP2’s dephosphorylation activity can influence downstream transcriptional regulation and STAT activation favorably. Phosphorylation controls the activity of JAK2 kinase in a site-dependent fashion. The IL3-driven JAK2-STAT5 signal is impaired in SHP2 mutant cells, yet wild-type SHP2 has the potential to reactivate this signal. The lack of SHP2 also strongly suppresses the activity of STAT5 (63, 64). SHP2 inactivation results in a decrease in both JAK2 activity and STAT5 phosphorylation (65). The JAK-STAT signal is inhibited when the Tyr1017 phosphorylation site of JAK combines with SOCS to generate a complex that stops JAK from binding to STAT. Through JAK’s tyrosine phosphorylation site dephosphorylation, SHP2 can stop JAK from attaching to SOCS and restart the STAT signaling cascade.

SHP2, however, also has the ability to inhibit the JAK-STAT pathway (7, 66). For example, SHP2 is drawn to the phosphorylated tyrosine residue pTyr759 of the gp130 cytokine receptor subunit, where it consequently can dephosphorylate STAT3, blocking JAK-STAT3 signaling, and IL-6-induced gene activation (67). Along this line, Ohtani et al. (62) showed that gp130-induced extension of STAT3 activation was present in animals devoid of SHP2 signaling, suggesting a negative function for SHP2 in JAK-STAT signaling.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a crucial transcription factor involved in transmitting signals from interleukin-1 (IL-1) and tumor necrosis factor (TNF) stimulation in various physiological and pathological processes (68, 69). The nuclear factor binding of light peptide gene enhancers generates inactive complexes and is in an inhibitory state in the basic state of NF-κB and B-cells inhibitor (IκB) (70). Phosphorylation of inhibitory-κB kinases (IKKs) by numerous kinases, such as AKT, mTOR, as well as mitogen-activated protein kinase (MAPK), lead to the activation of NF-κB (71–73). The transcriptional activity of NF-κB can be regulated by the RAS oncoprotein through its targeting of the transactivation domain of the NF-κB p65 subunit. SHP2 has been shown to be an essential component for the regulation of NF-κB in vivo. In the context of RAS mutant NSCLC, the activation of the NF-kB pathway upstream of IκB was induced by SHP2 inhibition. Within this particular framework, the inhibition of the SHP2-RAS-ERK pathway results in an upregulation of CXCR2 ligands that is dependent on NF-κB. This, in turn, results in the recruitment of S100A8^high granulocytic myeloid-derived suppressor cells (MDSCs), which exert suppressive effects on T cells (74).

It has been demonstrated that SHP2 is present in mitochondria, which are multipurpose organelles engaged in a number of biological functions such as energy synthesis, intermediate metabolism, cell apoptosis, and preservation of cytoplasmic calcium homeostasis (75, 76). However, most research efforts have concentrated on non-solid tumors and non-neoplastic disorders. For instance, Zang et al. (77) showed that alterations in the mitochondrial location of tyrosine kinase Src and tyrosine phosphatase SHP2 are responsible for sepsis-induced cardiac mitochondrial dysfunction. Protein tyrosine phosphatase PTPN11 tumor-related activation mutations increase mitochondrial metabolism, which causes oxidative stress and aging (78). Then, Guo et al. (79) found that SHP2 controls the stimulation of the NLR family pyridine-containing domain 3 (NLRP3) inflammasome negatively by affecting the homeostasis of the mitochondria, which is reliant on adenine nucleotide transferase 1 (ANT1). Considering the significance of mitochondria, SHP2’s influence on mitochondrial activity may play a part in mediating its involvement in solid tumors. However, currently there is little information available, therefore more research is necessary.

A small portion of SHP2 has been shown to be present in the nucleus, and there is evidence that SHP2 contributes to certain nuclear processes (80). SHP2 has the ability to trigger DNA damage-induced cell death and apoptosis, both of which are p53-independent processes. Furthermore, DNA damage-induced translocation of cell division cycle 25C (Cdc25C) from the nucleus to the cytoplasm requires SHP2 (81). Furthermore, it has been demonstrated that nuclear SHP2 controls STAT transcription factors. Through the nuclear interaction of SHP2 with telomerase reverse transcriptase (TERT), TERT is prevented from being exported from the nucleus, which decreases apoptosis sensitivity and prevents accelerated senescence of cells (80, 82). The aforementioned SHP2-mediated parafibromin dephosphorylation has also been reported to occur in the nucleus. The β-chain protein binds to dephosphorylated parafibromin, which is a part of the elongation factors PAF1 complex (PAF). When Wnt target genes are activated, the resultant parafibromin/β-catenin protein complex functions as a co-activator of T cell-specific transcription factor/lymphoid enhancer factor (TCF/LEF) (57).

Yes-associated protein (YAP) is linked to another nuclear function of SHP2. The nuclear accumulation of SHP2 is considerably facilitated by the interaction between dephosphorylated YAP and the transcription coactivator with PDZ binding motif (TAZ). SHP2 is kept in the cytoplasm by YAP/TAZ phosphorylation via Hippo signaling, which inhibits its nuclear function (83). The prognostic significance of SHP2 may be attributed to its nuclear localization and interaction with nuclear YAP1. This interaction activates the Wnt/ß-catenin signaling pathway, resulting in elevated expression of cyclin D1 and the c-myc (84).

In conclusion, SHP2 has been found in the nucleus across various contexts, including solid tumor types. This localization holds the potential to influence gene expression and may be crucial for cell proliferation, survival, and other facets of carcinogenesis. Future research should focus further on the function of nuclear SHP2 in epigenetic alterations, tumor growth, gene regulation, and therapeutic targets.

First of all, mutations that activate PTPN11 can actually be detected in lung cancer. E76V, E76K, V45L, and N58S were reported before (85–87). A variety of 23 distinct PTPN11 mutations were discovered when Richards et al. (87) recently analyzed PTPN11 mutations in 37 PTPN11-mutant non-small-cell lung cancer (NSCLC). The mutations were listed from high to low frequency: E76A, A72D, S502L, G503V, N58S, G60D, E76K, M82V, E225, E313, E412G, Y418, D425Y, H426R, V428M, A452S, G483D, Q500E, G503R, M504I, Y521F, D551N, D556N. Remarkably, exons account for 75% (26/37) of the NSCLC PTPN11 mutations, suggesting that the majority of PTPN11 mutations are functionally relevant in NSCLC. In a genetically modified mouse model, the PTPN11 E76K mutation is sufficient to cause NSCLC (86).

However, SHP2 appears to hold broader significance. In lung cancer tissue, wild-type SHP2 expression is markedly elevated compared to surrounding normal lung tissue, establishing a robust correlation between high SHP2 expression and lymph node metastasis. The overexpression of SHP2 might promote invasion and metastasis in NSCLC through processes like angiogenesis and lymphatic diffusion (88, 89). SHP2 knockdown lowers ERK phosphorylation and increases cell susceptibility to the EGFR inhibitor gefitinib in wild-type NSCLC cells expressing EGFR (90). As demonstrated by Dardaei et al. (91), where SHP2 inhibition prevents the reactivation of RAS and ERK1/2 following treatment with intermediate degenerative lymphoma kinase (ALK) inhibitors in NSCLC, the synergistic impact of combined RTK and SHP2 inhibitors appears to be a more general effect.

Furthermore, as shown by Mainardi et al. (8), knockout of PTPN11 in NSCLC cells has little effect on cell proliferation but increased sensitivity to MEK inhibition. In KRAS mutant NSCLC, blocking SHP2 can cause a senescence response, whereas inhibiting MEK can aggravate this process. More thorough analyses of SHP2 inhibitor treatment in KRAS- and EGFR-mutant NSCLC models revealed tumor-intrinsic CCL5/CXCL10 secretion. This secretion resulted in the depletion of alveolar and M2-like macrophages while inducing and promoting infiltration of B and T lymphocytes. This was not surprising, given the crosstalk of senescent cells with their immune environment. Furthermore, by simultaneously blocking the CXCR1/2-dependent import of immunosuppressive MDSCs, combination inhibition of SHP2 and CXCR1/2 may enhance antitumor T cell responses in NSCLC (74). Additionally, elevated SHP2 expression correlates with enhanced survival in advanced KRAS mutant NSCLC and serves as a predictor for the efficacy of PD-1/PD-L1 therapies (92).

In conclusion, SHP2 appears to be a promising therapeutic target in combination treatment methods for NSCLC since it plays a critical positive regulatory function in the incidence, metastasis, immune evasion, and drug resistance of lung cancer, regardless of individual RTK/RAS mutational status.

About 90% of PDAC tumors bear a KRAS mutation, which might encourage precancerous lesions associated with pancreatic cancer to progressively progress into invasive malignancy (93). Zheng et al. (94) used immunohistochemical techniques in order to assess the expression of SHP2 protein in 79 PDAC samples. Their results revealed that the proportion of PDAC tissues with high SHP2 expression was considerably greater (55.7 percent) than that of adjacent noncancerous tissues (10.1 percent). Additionally, it was observed that individuals with high expression of SHP2 had a shorter overall survival time in comparison to those with low expression. Studies have indicated a possible correlation between the onset and progression of PDAC and elevated expression of SHP2, indicating SHP2’s potential in both prognostic and therapeutic capacities. According to a different study, SHP2 expression is detectable for the duration of the PDAC tumor formation process. Furthermore, in a genetically altered mouse model, the generation of mutant KRAS-dependent PDAC was virtually entirely inhibited and survival time was markedly increased with deletion of PTPN11.

In established PDAC tumors, loss of SHP2 (or inhibition) sensitized to MEK inhibition and synergistically reduced tumor growth (6). Fedele et al. (95) discovered that SHP2 inhibition reduced RTK feedback signals and enhanced the action of KRAS^G12C inhibitors in PDAC. Furthermore, the SHP2-PDHA1-ROS axis is crucial for the upkeep of adipocytes and may regulate cytokine production as well as the proliferation of pancreatic cancer cells (96). Consequently, the majority of recent research points to a favorable association between SHP2 and the onset and progression of PDAC, indicating that SHP2 might be a desirable target in treatment combinations for this predominantly KRAS-mutated entity.

According to a preliminary study, the deficit in SHP2 specific for liver cells drives inflammatory signaling through the STAT3 pathway, resulting in tumor formation and regenerative proliferation in aged mice. Hepatocellular carcinoma (HCC) produced by diethylene nitrite (DEN) is considerably more likely to develop when SHP2 is absent, but this is eliminated when SHP2 and STAT3 are both absent at the same time in liver cells (7). According to this study, PTPN11/SHP2 may have a tumor-suppressive function in HCC that is driven by inflammation.

In addition, Chen et al. (97) have shown that Myc-driven HCC is dramatically aggravated in mice with hepatocyte-specific Ptpn11/Shp2 deletion.

Subsequent research revealed that liver cancer spheroids rich in patient-derived CSC as well as cancer stem cells (CSCs) selected for epithelial cell adhesion molecule (EpCAM) or differentiation cluster 133 (CD133) showed a substantial increase in SHP2. By encouraging the dedifferentiation of liver cancer cells and boosting the self-renewal of liver stem cells, upregulated SHP2 facilitates the proliferation of hepatic CSCs (98). According to this study, β-catenin signaling amplifies SHP2, which in turn stimulates the proliferation of hepatic CSC and the dedifferentiation of HCC cells. This information could be utilized to anticipate how a patient will react to chemotherapy. Furthermore, a recent study revealed that patient-derived xenografts and developed sorafenib-resistant cell lines have much higher levels of SHP2. By obstructing feedback pathways, the SHP2 inhibitor SHP099 may eradicate sorafenib resistance in organoid cultures and HCC cell lines (99). SHP2 inhibition decreases adaptive resistance to sorafenib by preventing the reactivation of the MEK/ERK and AKT signaling pathways induced by RTK, according to the findings of this study. In HCC, mTOR and SHP2 inhibition have been shown to have a similar synergistic impact (100).

Growth arrest and DNA damage 45G (GADD45G) were also reported to be generally downregulated in human and mouse HCC (101) and oncogene-transformed mouse liver cells. GADD45G ectopic expression significantly accelerates the aging process of HCC and suppresses tumor development in vivo. In human hepatocellular carcinoma cell lines, GADD45G expression strongly suppresses constitutive phosphorylation of STAT3 (Tyr⁷⁰⁵). Since GADD45G-induced STAT3 dephosphorylation was successfully reduced and senescence induction was greatly suppressed, it suggests that this action is reliant on SHP2.

Cholangiocarcinoma has been reported to have similar processes. Additionally, in this case, Sorafenib-induced dephosphorylation of Tyr⁷⁰⁵ STAT3 is mediated by SHP2, and in cholangiocarcinoma cells, Sorafenib-induced dephosphorylation of Tyr705 p-STAT3 is inhibited by knocking down SHP2. This increases tumor cell death (102).

Conversely, SHP2 has been demonstrated to function as a tumor suppressor by preventing YAP-mediated cholangiocarcinoma development (103).

Then, and this is crucial, SHP2 inhibitors can boost the antitumor innate immune system in liver cancer driven by RTKs by upregulating interferon-β Secretion, downregulating inflammatory cytokines, and inhibiting the chemokine receptor 5 signaling axis (104).

Consequently, SHP2 has two distinct functions in primary liver cancer: promoting and/or suppressing tumor growth in hepatocellular carcinoma and cholangiocarcinoma.

As a consequence, therapeutic approaches targeting SHP2 in liver cancer would need to be tailored in a context and time-dependent fashion.

According to related research, the expression rate of SHP2 in gastric cancerous tissues is notably greater than in healthy stomach mucosa (105). All identified cancer cell lines express SHP2 and certain diffuse gastric cancer (DGC) cell lines with MET or fibroblast growth factor receptor 2 (FGFR2) gene amplification exhibit preferential tyrosine phosphorylation. Treatment with MET or FGFR inhibitors or their deletion significantly reduces SHP2 tyrosine phosphorylation. In a mouse xenograft model, pharmacological inhibition or suppression of SHP2 effectively inhibits the migratory, invasive, and peritoneal dissemination of DGC cells that are dependent on MET (106).

Significant overexpression of KRAS protein was seen in the KRAS amplified gastroesophageal adenocarcinoma (GEAC) model. While being resistant to MAPK inhibition, mechanistically the model was able to respond adaptively by quickly boosting KRAS GTP levels. The adaptation process was decreased by the suppression of guanine exchange factors SOS1 and SOS2 or protein tyrosine phosphatase SHP2, and the model became more sensitive to MEK inhibition when these components were targeted, as shown by Wong et al. (107).

With regards to KRAS mutant gastric cancer, Zheng et al. (30) recently discovered that, via suppressing KSR1 activity, SHP2 inhibition mitigates adaptive resistance to MEK inhibitors.

A different role for SHP2 in human esophageal squamous cell carcinoma (ESCC) was discovered by Xu et al. (67). SHP2 expression appeared to be frequently downregulated in ESCC tissues. Additionally, patients exhibiting low SHP2 expression experienced poorer overall survival (OS) compared to those with higher SHP2 expression levels. SHP2’s functional implications for blocking inflammatory STAT3-signaling appear to be predominant in this context. By dephosphorylating STAT3, SHP2 appears to impair growth and progression of ESCC.

In conclusion, SHP2 is recognized for its oncogenic function in the genesis and advancement of GEAC, but not in ESCC. Furthermore, it could be a clinical treatment target for GEAC and ESCC as well as a prognostic marker.

Early research revealed that colorectal adenomas and stage 1 tumors had much higher levels of SHP2 expression than did later advanced cancers (108). SHP2 may have opposing effects in the large intestine cancer: depending on the inflammatory milieu, it may either stimulate or prevent tumor growth. The proliferation, invasion, and tumor properties of intestinal epithelial cells (IECs) derived from human colorectal cancer cells (CRC) and carcinogenic KRAS are inhibited by SHP2 silencing. SHP2 was required in IEC and CRC cells harboring oncogenic KRAS for full activation of MEK/ERK signaling. In addition, inhibition or knockout of PTPN11 confers sensitivity to BRAF inhibition in BRAF mutant colon cancer (109).

Conversely, Huang et al. (110) were able to show that SHP2 inhibits the proliferation and migration of CRC cells by dephosphorylating STAT3. As per the findings, SHP2 inhibition and knockdown boost cellular signaling in HCT-116 colorectal cancer cells, hence promoting their proliferation both in vitro as well as in vivo (111).

The following two examples further highlight the difficulty in identifying and discerning tumor-promoting and tumor-suppressing functions, even though targeting SHP2 in frank colon cancer may be beneficial: first, SHP2 appeared to worsen the activation of the interferon gene stimulatory factor (STING) pathway by limiting the DNA repair mediated by poly ADP-ribose-polymerase 1 (PARP1) in colorectal cancer cells, indicating that SHP2 agonist lovastatin combined with chemotherapy is a viable treatment option for colorectal cancer (112). Second, and in contrast, cetuximab and EGFR-targeted therapy has long been an approved treatment protocol for RAS wild-type, metastatic colorectal cancer, and SHP2 inhibitors reliant on phospholipase C gamma 1 (PLCg1) exhibit anti-tumor effects in cancer cells resistant to cetuximab (113).

As a consequence, SHP2 inhibition approaches in colorectal cancer, although promising, may have mixed effects and need to be closely monitored with respect to their intended beneficial and potentially detrimental components.

Research has also been done on the function of SHP2 in the progression of oral cancer, particularly oral squamous cell carcinoma (OSCC) (114). SHP2 protein expression is significantly increased in OSCC tissues compared to normal tissues. This overexpression is correlated to clinical staging and lymph node metastasis in advanced tumors. By controlling the expression of proteins linked to apoptosis, inhibiting SHP2 expression in vitro can cause cell death and reduce OSCC cell viability and invasion (115). Further, research has demonstrated that SHP2 promotes the metastasis of oral cancer cells. This suggests that the SHP2-ERK1/2-Snail/Twist1 pathway may play a significant role in the invasion and metastasis of oral cancer (116). In addition, deletion of SHP2 also exhibits significantly reduced metastatic capacity in OSCC.

In conclusion, SHP2 could be an oncogenic gene that encourages OSCC metastases. It may be investigated further as a biomarker for estimating how OSCC will develop, and focusing on SHP2 has been proposed as a novel approach for OSCC clinical management in the future.

It was discovered that SHP2 contributes to proliferative signals for laryngeal cancer cells as well, a process which is, again, mainly mediated via the MAPK pathway (117). Thus, SHP2 may contribute to the carcinogenicity of laryngeal cancer through involvement in the RAS/RAF/MEK/ERK signaling pathway and could be a useful target for therapy.

After examining 65 individuals with thyroid cancer (TC), Hu et al. (118) discovered that the samples and cell lines of thyroid cancer patients had elevated levels of SHP2. In the meanwhile, the findings demonstrated a strong association between high SHP2 expression and lymph node metastases, high TNM staging, and tumor differentiation.

On the other hand, TC patients with SHP2 overexpression had a reduced probability of passing away from the illness than did TC patients with low SHP2 expression, according to findings by Cao et al. (119). SHP2 expression did not, however, function as an independent predictive factor in multivariate analysis.

SHP2 blockade can overcome MEK inhibitor resistance, consistent with the findings of studies on other tumor types and leads to TC growth suppression that is persistent, particularly in differentiated thyroid carcinoma (DTC) cells (120). On the basis of these concepts, Ma et al. (121) recently showed that vemurafenib-induced cancer sensitivity was enhanced by inhibiting SHP2, which also reversed the reactivation of the MAPK/ERK signaling cascade brought on by RTK activation.

It’s interesting to note that, because SHP2 is necessary to propagate the PD-1 signal in this context, blocking the PD-1 circuit in TC might directly harm the proliferation of TC cells expressing PD-1. This inhibition would not only suppress the RAS/MAPK signaling pathway but also may restore anti-cancer immunity (122).

When considered together and in light of recent findings, SHP2 seems to be involved in the carcinogenesis of thyroid cancer, and blocking it might be a useful adjunctive therapeutic approach.

Research indicates that SHP2 is one of the essential signal transduction molecules that activate the RAS/ERK pathway in breast cancer as well and that this pathway plays a significant role in the occurrence and progression of breast cancer (123). For the first time, Zhou and Agazie (124) hypothesized that breast cancer cells had elevated levels of SHP2. They found that inhibiting SHP2 resulted in reduced EGF-induced RAS/ERK and PI3K/AKT signaling pathways, and brought back the typical phenotype of differentiated breast epithelium. The inhibition of SHP2 resulted in the downregulation of the mesenchymal markers vimentin and fibronectin and the upregulation of the epithelial marker E-cadherin. These findings suggest that SHP2 actively regulates mitosis, cell survival signaling, and EMT, hence promoting the phenotype of cancer cells. Therefore, it is not surprising, that SHP2 is overexpressed in invasive ductal carcinoma (IDC) breast tumors and is positively connected with lymph node metastasis, nuclear hormone receptor accumulation, and higher tumor grade (125).

SHP2 deletion inhibits the progression of breast cancer and decreases metastasis (126). Knockout of SHP2 also suppresses ErbB2-induced mammary tumorigenesis (127). In addition, SHP2 knockout attenuates the activation of PI3K/AKT signaling and causes the dephosphorylation and resultant activation of GSK3β in breast cancer cells (128).

In the early phases of triple-negative breast cancer (TNBC), SHP2 plays a crucial mediating role. This is because a shortage in SHP2 activates many SRC family kinases and downstream substrates, which hinder various aspects of tumor cell motility such as invasion, chemotaxis, migration, and velocity (129). A novel substance that suppresses SHP2 and cyclin-dependent kinase 4 (CDK4), downregulates pERK and pRb expression, and boosts immunological function has been shown in recent research to prevent the development of TNBC (130). ETS oncogene 1 (ETS1) activity is decreased in TNBC cell lines when SHP2 is inhibited because it blocks the MAPK signaling cascade, which in turn downregulates IL-8 production (131). In TNBC, SHP2 knockout cells reconstituted with a phosphatase-dead SHP2 mutant are unable to (re-)activate AKT and MAPK signaling upon treatment with BYL719, which makes them sensitive to PI3K inhibition (132). Additionally, drug-resistant cells quickly restart both pathways following PI3K inhibitor monotherapy, whereas combined inhibition of PI3K and SHP2 inhibits proliferation and results in prolonged inactivation of PI3K and MAPK signaling.

Lastly, β-catenin stability might be a further mechanism by which SHP2 promotes TNBC.

In summary, SHP2 plays a vital role in modulating breast cancer development, invasion and metastasis and may be a meaningful therapeutic target in different histological entities of this disease.

In cervical cancer tissues infected with human papillomavirus, SHP2 expression was significantly greater (88.8%) compared to tissues from cervical intraepithelial neoplasia (CIN) (62.5%) and normal cervixes (45%) (133). Furthermore, SHP2 stimulates the initiation and advancement of cervical cancer by preventing IFN-β from being produced, consequently fostering the proliferation of cervical cancer cells (134). Another finding showed that in human cervical cancer cells, SHP2 inhibition has anti-proliferative/anti-migratory effects through the RAS/RAF/ERK and PI3K/AKT pathways (135). Additionally, by triggering autophagy to break down damaged mitochondria and the ubiquitin ligase Parkin to prevent chemotherapy-induced apoptosis in cervical cancer, SHP2 takes part in chemoprotection (136). Through suppressing the activation of PI3K/AKT and NF-κB signaling pathways, the combination of an SHP2 inhibitor and 5-fluorouracil (5-FU) can synergistically induce apoptosis and impede the proliferation of cervical cancer cells (137). In addition, deletion of SHP2 in cervical cancer cells promotes reprogramming of glutamine metabolism (138). When combined, these signaling pathways may allow SHP2 to play an oncogenic function in cervical cancer that can be therapeutically exploited.

Ovarian cancer cell lines exhibit higher levels of SHP2 expression compared to normal ovarian epithelial cell lines. Additionally, lymph node metastasis, distant metastases, clinical staging, and histological grading were all correlated with SHP2 expression (139). Elevated SHP2 expression in ovarian cancer cell lines has been demonstrated to enhance cell migration, invasion, and proliferation, potentially via the activation of AKT. In contrast, SHP2 inhibition specifically reduced ERK1/2 activity, ovarian cancer cells expressing GAB2, and their ability to proliferate. Furthermore, SHP2 inhibitors and PI3K inhibitors combine to prevent the growth and survival of GAB2-overexpressing ovarian cancer cells both in vitro as well as in vivo (140). Li et al. (141) noted that the autophagy inhibitor elaiophylin triggers ER-stress and paraptosis by binding directly to SHP2 and thereby triggering toxic hyperactivation of the SHP2/SOS1/MAPK pathway. Then taking advantage of already-elevated MAPK levels in drug-resistant ovarian cancer cells, elaiophylin overcame resistance to chemotherapy in ovarian cancer. Furthermore, very recently, Rossini et al. (142) demonstrated that tyrosine phosphorylation and the association of indoleamine 2,3‐dioxygenase 1 (IDO1) with SHP2 were significantly increased in SKOV-3 cells in response to the IDO1-inhibitor and -stabilizer epacadostat. Meanwhile, in SKOV-3 cells treated with epacadostat the signaling triggered by the transducing molecular complex IDO1-SHP2 accelerates the migratory capacity and the colony-forming ability of SKOV-3 cells, suggesting a pro-tumorigenic phenotype. These findings demonstrate the carcinogenic participation of SHP2 in the formation of ovarian tumors and substantiate the therapeutic promise of targeting this phosphatase in ovarian cancer.

Four distinct prostate cancer cell lines and specimens from 122 prostate cancer patients were examined by Tassidis et al. (143). The findings suggest that enhanced prostate cancer development and progression are linked to the decrease of cytoplasmic SHP2 expression. Conversely, it has been shown that SHP2 is overexpressed in prostate cancer, which is linked to unfavorable clinical outcomes (such as tumor spread and a reduced patient survival time). Increased tumor growth in vivo, colony and spheroid formation, and proliferation of prostate cancer cells can result from overexpressing wild-type or oncogenic SHP2 mutations. Furthermore, by weakening the PAR3/PAR6/aPKC polar protein complex as well as promoting EMT, SHP2 can encourage the migration of prostate tumor cells both in vivo and in vitro, as well as the spread of prostate cancer (144). Targeting SHP2 increases expression of PD-L1 and human leukocyte antigen (HLA) ABC in prostate cancer cells by phosphorylating STAT1, which is relevant to immune-cell interaction and immunotherapy tactics (145).

In conclusion, there is ongoing debate over the involvement of SHP2 in prostate cancer. A more thorough study is needed to identify the precise, and maybe context-dependent, function that SHP2 plays in this disease.

Common mutations in NRAS and BRAF observed in melanoma activate the RAS/RAF/MAPK and PI3K/AKT signaling pathways (146, 147). Phosphorylated AKT levels exhibit a negative correlation with patient survival rate and rise markedly during the invasion and spread of melanoma (148). Additionally, SHP2 mutations and overexpression were discovered in melanoma patient samples (149). Zhang et al. (150) noted that SHP2 activates the ERK1/2 and AKT signaling pathways to support the survival, motility, and anchoring independent proliferation of melanoma cells. Additionally, they showed that SHP2 suppression slowed the development of xenograft melanoma by enhancing tumor cell death and reducing tumor cell proliferation.

When combined, SHP2 seems to have an oncogenic function in melanoma and presents a viable new target for melanoma combination treatment, which includes tumors with NRAS and BRAF mutations.

The signaling pathways of RTKs, including EGFR, PDGFR, and/or c-MET, are often modified throughout the pathogenesis of glioblastoma multiforme (GBM) (151, 152). In a spontaneous transgenic high-activity HRAS glioma mouse model, inhibition of SHP2 can reduce the development from low-grade astrocytoma to GBM (153). SHP2-dependent pathway inhibition of cellular senescence may be a significant contributing element to establishment of GMB (154). In response to the co-inhibition of EGFR and c-MET, Furcht et al. (155) observed that knocking down SHP2 decreased the proliferative rate of GBM cell lines. SHP2-mediated ERK activity predominated in this context. Furthermore, the co-inhibition of EGFR and c-MET induces cell death, where the SHP2-mediated inhibition of STAT3 plays a crucial role. UBE2D3, a ubiquitin-binding enzyme implicated in the etiology of several malignancies, has the ability to stimulate SHP2 ubiquitination. This, in turn, raises the output of the STAT3 pathway, hence promoting the growth and development of gliomas (156).

In conclusion, selective and careful targeting of SHP2 may have therapeutic implications for the treatment of GBM, given the functional involvement of SHP2 in the onset and progression of the illness.

The roles in different solid tumor entities are illustrated in Figure 3 .

Endothelial cells are structural elements of the vascular system, supplying blood to tissues and becoming ready to react to external harm. They are located on the inside surface of blood arteries. There has been much research done on the function of SHP2 in endothelial processes. SHP2 interacts with VE-cadherin and VEGFR in endothelial cells, which is essential for angiogenesis and the function of the endothelial barrier (183, 184). The context-dependent function of SHP2 as a negative regulator of VEGFR2 signaling and angiogenesis emphasizes the need for more study because VEGF/VEGFR2 regulation is complicated (185). SHP2 modulates the production of pro-angiogenic SRY-Box transcription factor 7 (SOX7) and pathological angiogenesis through apoptosis signal-regulated kinase 1 (ASK1)-c-Jun signaling (186). By downregulating the production of SOX7, which promotes angiogenesis, SHP2 deficiency harms tubular formation, migration, and proliferation of endothelial cells. Tumor development, angiogenesis, and vascular anomalies are all restored in SHP2-deficient animals when SOX7 is re-expressed in SHP2 knockdown cells. Thus, in the tumor vascular system, SHP2 plays a crucial role in altering endothelial cells’ development and survival.

SHP2 promotes proliferative ERK1/2 signaling and suppresses pro-apoptotic STAT3 (187). Systemic SHP2 inhibition increases tumor necrosis, decreases tumor blood vessels and blood perfusion, and promotes tumor vascular system degradation and blood extravasation in animals harboring SHP2-independent tumor cell proliferation of the chosen tumor type.

The current findings highlight the prospect that targeting SHP2 in tumor blood vessel support may be a particularly effective approach and imply that targeting SHP2 may represent a unique strategy for targeting endothelial cells in the tumor vasculature.

Fibroblasts are linked to cancer cells at different phases of the growth of solid tumors, and their structural and functional roles in this process, with all of its intricacies and dual impacts of supporting and restraining tumors, are just now coming to light. With more and more cancer-associated fibroblast (CAF) subtypes being identified, the particular function and contribution of the ubiquitously expressed tyrosine phosphatase SHP2 within each CAF cell type should be carefully elucidated. So far, knowledge for CAFs is very scarce. However, in normal non-tumor-associated fibroblasts, SHP2 appears to play similar roles as e.g. in epithelial cells, being required for full activation of the MAPK/ERK pathway in response to growth factors, FGFs and PDGFs being the most important players for fibroblasts (188). In addition, very recently, Mucciolo et al. (189) demonstrated EGFR-expression and EGFR-dependent activation of a CAF subtype in pancreatic cancer (the myofibroblastic CAFs, or myCAFs), promoting local metastasis. It is very reasonable to hypothesize that SHP2 is involved in signal transduction in this context. To fully decipher the in vivo therapeutic benefits of SHP2-inhibition for solid tumors, it is therefore crucial to comprehend the functional role of SHP2 in all different CAF subtypes.