PTPN11

Official Full Name

protein tyrosine phosphatase non-receptor type 11

Organism

Homo sapiens

GeneID

5781

Background

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

Synonyms

CFC; NS1; JMML; SHP2; BPTP3; PTP2C; METCDS; PTP-1D; SH-PTP2; SH-PTP3;

Bio Chemical Class

Phosphoric monoester hydrolase

Protein Sequence

MTSRRWFHPNITGVEAENLLLTRGVDGSFLARPSKSNPGDFTLSVRRNGAVTHIKIQNTGDYYDLYGGEKFATLAELVQYYMEHHGQLKEKNGDVIELKYPLNCADPTSERWFHGHLSGKEAEKLLTEKGKHGSFLVRESQSHPGDFVLSVRTGDDKGESNDGKSKVTHVMIRCQELKYDVGGGERFDSLTDLVEHYKKNPMVETLGTVLQLKQPLNTTRINAAEIESRVRELSKLAETTDKVKQGFWEEFETLQQQECKLLYSRKEGQRQENKNKNRYKNILPFDHTRVVLHDGDPNEPVSDYINANIIMPEFETKCNNSKPKKSYIATQGCLQNTVNDFWRMVFQENSRVIVMTTKEVERGKSKCVKYWPDEYALKEYGVMRVRNVKESAAHDYTLRELKLSKVGQGNTERTVWQYHFRTWPDHGVPSDPGGVLDFLEEVHHKQESIMDAGPVVVHCSAGIGRTGTFIVIDILIDIIREKGVDCDIDVPKTIQMVRSQRSGMVQTEAQYRFIYMAVQHYIETLQRRIEEEQKSKRKGHEYTNIKYSLADQTSGDQSPLPPCTPTPPCAEMREDSARVYENVGLMQQQKSFR

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

9 +

Discontinued Drug

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Detailed Information

The PTPN11 gene is located on human chromosome 12q24.13 and encodes a non-receptor protein tyrosine phosphatase known as SHP-2. Structurally, SHP-2 is highly conserved, containing two tandem Src homology 2 (SH2) domains, N-SH2 and C-SH2, as well as a catalytic protein tyrosine phosphatase (PTP) domain. Under physiological conditions, the N-SH2 domain interacts intramolecularly with the PTP domain to maintain an autoinhibited conformation, keeping the enzyme inactive. Upon stimulation of cell surface receptors by extracellular growth factors or cytokines, SHP-2 recognizes and binds to phosphorylated tyrosine residues on receptor intracellular domains via its SH2 domains. This binding induces a conformational change that relieves autoinhibition and activates phosphatase activity. This precise molecular switch enables SHP-2 to regulate multiple intracellular signaling pathways, including RAS-MAPK, JAK-STAT, and PI3K-AKT, thereby playing a central role in fundamental cellular processes such as growth, differentiation, metabolism, and migration.

Figure 1. SHP2 molecular structure showing its functional domains and conformational changes between inhibited and activated states. (Chen X, et al., 2024)

Physiological Roles in Hematopoiesis and Immune Function

SHP-2’s physiological function is particularly prominent in the hematopoietic system. It is essential for the maintenance and self-renewal of hematopoietic stem cells, regulating the balance of the hematopoietic system by modulating signals from various growth factors and cytokine receptors, including EPO, TPO, and GM-CSF. In immune cells, SHP-2 participates in T cell receptor signaling, controlling the activity of kinases such as FYN and LCK through dephosphorylation, thereby influencing T cell differentiation and activation. SHP-2 also interacts with adaptor proteins such as GAB1 and GAB2 to form signaling complexes that regulate downstream effector activation and signal amplification, serving as a critical node connecting cell surface receptors with intracellular signaling networks.

Figure 2. SHP2signalingpathways. (Chen X, et al., 2024)

Mutational Features and Pathogenic Mechanisms

Mutations in PTPN11 exhibit distinct patterns across different disease contexts. In hematologic malignancies, most PTPN11 mutations occur in the N-SH2 domain, particularly at hotspot residues in exon 3, including p.A72D and p.E76K. These mutations disrupt the intramolecular interaction between the N-SH2 and PTP domains, rendering SHP-2 constitutively active and resulting in persistent activation of downstream pathways, especially the RAS-MAPK pathway. Molecularly, PTPN11 mutations frequently co-occur with NPM1, NRAS, FLT3-ITD, and DNMT3A mutations, indicating that PTPN11 mutations are usually part of a complex molecular landscape contributing to leukemia pathogenesis.

In developmental disorders, germline PTPN11 mutations are the most common cause of Noonan syndrome. Unlike somatic mutations in leukemia, these germline mutations mildly increase SHP-2 activity, sufficient to perturb development without directly inducing malignancy. Noonan syndrome patients typically exhibit distinctive facial features, short stature, congenital heart defects (notably pulmonary valve stenosis and hypertrophic cardiomyopathy), and hematologic abnormalities. PTPN11 mutations are also closely associated with juvenile myelomonocytic leukemia (JMML), a rare pediatric myeloproliferative neoplasm characterized by abnormal proliferation of granulocytes and monocytes.

Clinical Prognostic Significance and Therapeutic Challenges

PTPN11 mutations have clear adverse prognostic implications in hematologic malignancies. In MDS, patients with PTPN11 mutations exhibit higher rates of leukemic transformation compared with wild-type patients, reflecting increased genomic instability and significantly shorter overall survival. In AML, patients harboring PTPN11 mutations show lower complete remission rates, particularly in intensified induction therapy subgroups.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential means to improve outcomes. PTPN11-mutant AML patients receiving allo-HSCT have a median overall survival of 24 months, significantly better than 5.3 months in patients receiving chemotherapy alone, supporting early consideration of transplantation as a consolidation strategy in high-risk cases.

Targeted therapies for SHP-2 have advanced, particularly the development of allosteric inhibitors such as SHP099, which stabilize SHP-2’s autoinhibited conformation. Preclinical studies demonstrate efficacy against PTPN11-mutant leukemia cells. However, clinical application faces dual challenges: managing toxicity due to SHP-2’s essential physiological functions and addressing the complex interactions of mutant SHP-2 with other signaling molecules, including RAS and FLT3. Current strategies under investigation include developing more selective SHP-2 inhibitors and designing combination therapies targeting PTPN11-mutant leukemia, such as pairing SHP-2 inhibitors with MEK or FLT3 inhibitors.

Reference

Chen X, Keller SJ, Hafner P, et al. Tyrosine phosphatase *PTPN11/*SHP2 in solid tumors - bull's eye for targeted therapy? Front Immunol. 2024 Mar 5;15:1340726.
Yang W, Lefebvre V. PTPN11 in cartilage development, adult homeostasis, and diseases. Bone Res. 2025 May 16;13(1):53.

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