PTPN11 (SHP-2): A Key Signaling Phosphatase in Development and Disease
Comprehensive genomic, functional, and clinical overview of the PTPN11 gene, encoding the non-receptor protein tyrosine phosphatase SHP-2, with implications in Ras-MAPK signaling, developmental disorders, and cancer.
Gene Information Card
| Symbol | PTPN11 |
|---|---|
| Full Name | protein tyrosine phosphatase non-receptor type 11 |
| Gene Type | protein coding |
| Chromosomal Location | 12q24.13 |
| NCBI Gene ID | 5781 ncbi.nlm.nih.gov/gene/5781 |
| Ensembl ID | ENSG00000178145 |
| UniProt ID | Q06124 |
| OMIM ID | 176876 |
| HGNC ID | 9644 |
| Aliases | SHP-2, SHP2, PTP-1D, PTP2C, BPTP3, CFC, NS1 |
Description
PTPN11 encodes the non-receptor protein tyrosine phosphatase SHP-2, a critical signaling enzyme that regulates various cellular processes including proliferation, differentiation, migration, and survival. SHP-2 contains two Src homology-2 (SH2) domains, a protein tyrosine phosphatase (PTP) domain, and a C-terminal tail with tyrosine phosphorylation sites. It is a key component of the Ras-MAPK signaling pathway, acting downstream of receptor tyrosine kinases and cytokine receptors. Mutations in PTPN11 are associated with developmental disorders such as Noonan syndrome and LEOPARD syndrome, as well as with certain leukemias and solid tumors.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Noonan syndrome | Gain-of-function mutations in PTPN11 lead to hyperactivation of the Ras-MAPK pathway, causing developmental abnormalities. | ClinVar, OMIM |
| LEOPARD syndrome | Mutations in PTPN11, often with loss of catalytic activity, result in a distinct phenotype with cardiac and skin abnormalities. | ClinVar, OMIM |
| Juvenile myelomonocytic leukemia (JMML) | Somatic gain-of-function mutations in PTPN11 are found in about 35% of JMML cases, leading to constitutive activation of the Ras pathway. | COSMIC, ClinVar |
| Acute myeloid leukemia (AML) | Somatic mutations in PTPN11 are present in a subset of AML cases, contributing to aberrant signaling. | COSMIC, ClinVar |
| Myelodysplastic syndromes (MDS) | PTPN11 mutations are observed in some MDS cases, often associated with disease progression. | COSMIC, ClinVar |
| Lung cancer | Somatic mutations in PTPN11 have been identified in lung cancer, potentially activating the MAPK pathway. | COSMIC |
| Colorectal cancer | PTPN11 mutations are found in a small percentage of colorectal cancers, contributing to tumorigenesis. | COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 12.5 | Medium |
| Kidney | 10.2 | Medium |
| Liver | 8.4 | Low |
| Lung | 9.1 | Low |
| Brain | 7.8 | Low |
| Skeletal Muscle | 6.5 | Low |
| Testis | 15.3 | Medium |
| Thyroid | 11.0 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K-562 (leukemia) | 18.2 | High expression |
| HeLa (cervical cancer) | 12.4 | Moderate expression |
| A549 (lung cancer) | 10.1 | Moderate expression |
| MCF7 (breast cancer) | 9.8 | Moderate expression |
| HepG2 (liver cancer) | 8.5 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Asn308Asp (N308D) | Missense | Germline; common in Noonan syndrome | Gain-of-function; enhances ERK activation |
| p.Gln506Pro (Q506P) | Missense | Germline; Noonan syndrome | Gain-of-function; increased phosphatase activity |
| p.Glu76Lys (E76K) | Missense | Somatic; JMML, AML | Gain-of-function; constitutive activation |
| p.Thr73Ile (T73I) | Missense | Somatic; JMML | Gain-of-function; hyperactivation |
| p.Tyr279Cys (Y279C) | Missense | Germline; LEOPARD syndrome | Loss-of-function; reduced catalytic activity |
| p.Thr468Met (T468M) | Missense | Germline; LEOPARD syndrome | Loss-of-function; dominant-negative effect |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in PTPN11, such as those causing LEOPARD syndrome, typically reduce or abolish the catalytic activity of SHP-2. These mutations often affect the PTP domain, impairing its ability to dephosphorylate substrates. The resulting decrease in signaling can lead to developmental defects, particularly in cardiac and skeletal tissues.
Gain of Function (GOF)
Gain-of-function mutations, commonly found in Noonan syndrome and various cancers, increase the phosphatase activity of SHP-2 or promote its constitutive activation. These mutations often occur in the N-SH2 domain, disrupting autoinhibition and leading to hyperactivation of the Ras-MAPK pathway, promoting cell proliferation and survival.
Dominant Negative (DN)
Some PTPN11 mutations, particularly those associated with LEOPARD syndrome, exhibit a dominant-negative effect. These mutant proteins can bind to substrates but lack catalytic activity, thereby interfering with the function of the wild-type SHP-2 and downstream signaling. This leads to a reduction in MAPK pathway activity, contrasting with the gain-of-function seen in Noonan syndrome.
View complete mutation data：
Gene Ontology (GO)
| • protein tyrosine phosphatase activity | • SH2 domain binding |
| • signal transduction | • Ras protein signal transduction |
| • cell proliferation | • cell differentiation |
| • positive regulation of MAPK cascade | • negative regulation of MAPK cascade |
| • insulin receptor signaling pathway | • growth hormone receptor signaling pathway |
Pathways
• Ras-MAPK signaling pathway
• ErbB signaling pathway
• Insulin signaling pathway
• Growth hormone signaling pathway
• Cytokine-cytokine receptor interaction
• T cell receptor signaling pathway
• B cell receptor signaling pathway
• PDGF signaling pathway
Protein Summary
The PTPN11 protein, SHP-2, is a ubiquitously expressed non-receptor protein tyrosine phosphatase that plays a pivotal role in signal transduction. It contains two SH2 domains that mediate its interaction with phosphorylated tyrosine residues on receptors and adaptor proteins, leading to its activation. SHP-2 positively regulates the Ras-MAPK pathway by dephosphorylating specific targets, such as RAS p21 protein activator 1 (RASA1) and sprouty proteins, thereby promoting cell growth and differentiation. It also participates in other signaling cascades, including JAK-STAT and PI3K-AKT pathways. Dysregulation of SHP-2 activity due to mutations contributes to various human diseases, including developmental syndromes and cancer.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PTPN11 Knockout HAP1 Cell Line | EDJ-KQ78119 | Human | 5781 | Details Get a Quote |
| PTPN11 Knockout HEK293T Cell Line | EDJ-KQ78166 | Human | 5781 | Details Get a Quote |
Displaying Records 1 To 2 Of 2 Records
