Biology:PTPN11

Short description: Protein-coding gene in humans

Generic protein structure example

Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D), Src homology region 2 domain-containing phosphatase-2 (SHP-2), or protein-tyrosine phosphatase 2C (PTP-2C) is an enzyme that in humans is encoded by the PTPN11 gene. PTPN11 is a protein tyrosine phosphatase (PTP) Shp2.

PTPN11 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.

Evolution: Although lost in rodents and higher primates, most jawed vertebrates, including sharks, have a second ancient molecule that is very similar to PTPN11 (SHP-2) and has been named SHP-2like (SHP-2L). In zebrafish, SHP-2 and SHP-2L have overlapping functional abilities. SHP-2 and SHP-2L are quite distinct from SHP-1 (PTPN6).

Structure

PTPN11 encodes the protein tyrosine phosphatase SHP2, which has a modular structure essential for its regulatory function in cell signaling. SHP2 consists of two tandem Src homology 2 (SH2) domains at the N-terminus (N-SH2 and C-SH2), followed by a catalytic protein tyrosine phosphatase (PTP) domain and a C-terminal tail containing tyrosyl phosphorylation sites. In its inactive, auto-inhibited conformation, the N-SH2 domain binds intramolecularly to the PTP catalytic domain, blocking substrate access to the active site. Upon binding to phosphotyrosyl residues on target proteins, the N-SH2 domain undergoes a conformational change that releases the PTP domain, thereby activating the enzyme. The catalytic domain itself adopts a conserved fold characteristic of classical PTPs, featuring a catalytic loop (WPD loop) that undergoes conformational changes during substrate binding and catalysis. This structural arrangement allows SHP2 to tightly regulate signaling pathways by selectively dephosphorylating substrates involved in cell growth, differentiation, and migration. Mutations disrupting the interface between the N-SH2 and PTP domains can lead to constitutive activation or impairment of SHP2, underlying diseases such as Noonan syndrome and certain leukemias. The overall structure has been elucidated by multiple crystallographic studies, revealing both the auto-inhibited and active states, which provide insight into its mechanism of regulation and function in diverse cellular contexts.

Function

PTPN11 encodes SHP2, a ubiquitously expressed protein tyrosine phosphatase that plays an important role in regulating cell signaling pathways, most notably the RAS/MAPK cascade, which controls cell proliferation, differentiation, migration, and survival. SHP2 acts as a positive regulator of signal transduction by dephosphorylating specific phosphotyrosine residues on target proteins, thereby facilitating the propagation of growth factor and cytokine signals. During embryonic development, SHP2 is essential for the formation of the heart, blood cells, bones, and other tissues. Germline mutations in PTPN11 cause developmental disorders such as Noonan syndrome and LEOPARD syndrome, while somatic mutations are frequently implicated in hematologic malignancies and solid tumors by promoting aberrant activation of oncogenic pathways. In cancer, SHP2 can function as an oncogenic driver by sustaining RAS/RAF/MAPK signaling and supporting tumor cell growth and survival. Thus, PTPN11/SHP2 is a critical regulator of both normal cellular processes and disease states, with its dysregulation contributing to developmental syndromes and oncogenesis.

Clinical significance

Missense mutations in the PTPN11 locus are associated with both Noonan syndrome and Leopard syndrome. At least 79 disease-causing mutations in this gene have been discovered.

Noonan syndrome

In the case of Noonan syndrome, mutations are broadly distributed throughout the coding region of the gene but all appear to result in hyper-activated, or unregulated mutant forms of the protein. Most of these mutations disrupt the binding interface between the N-SH2 domain and catalytic core necessary for the enzyme to maintain its auto-inhibited conformation.

Leopard syndrome

The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants. It is currently unclear how mutations that give rise to mutant variants of Shp2 with biochemically opposite characteristics result in similar human genetic syndromes.

Metachondromatosis

It has also been associated with metachondromatosis.

Cancer

Patients with a subset of Noonan syndrome PTPN11 mutations also have a higher prevalence of juvenile myelomonocytic leukemias (JMML). Activating Shp2 mutations have also been detected in neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, lung cancer, colorectal cancer. Recently, a relatively high prevalence of PTPN11 mutations (24%) were detected by next-generation sequencing in a cohort of NPM1-mutated acute myeloid leukemia patients, although the prognostic significance of such associations has not been clarified. These data suggests that Shp2 may be a proto-oncogene. However, it has been reported that PTPN11/Shp2 can act as either tumor promoter or suppressor. In aged mouse model, hepatocyte-specific deletion of PTPN11/Shp2 promotes inflammatory signaling through the STAT3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and spontaneous development of tumors. Decreased PTPN11/Shp2 expression was detected in a subfraction of human hepatocellular carcinoma (HCC) specimens. The bacterium Helicobacter pylori has been associated with gastric cancer, and this is thought to be mediated in part by the interaction of its virulence factor CagA with SHP2.

H Pylori CagA virulence factor

CagA is a protein and virulence factor inserted by Helicobacter pylori into gastric epithelia. Once activated by SRC phosphorylation, CagA binds to SHP2, allosterically activating it. This leads to morphological changes, abnormal mitogenic signals and sustained activity can result in apoptosis of the host cell. Epidemiological studies have shown roles of cagA- positive H. pylori in the development of atrophic gastritis, peptic ulcer disease and gastric carcinoma.

Interactions

PTPN11 has been shown to interact with

• CagA,
• Cbl gene,
• CD117,
• CD31,
• CEACAM1,
• Epidermal growth factor receptor,
• Erk
• FRS2,
• GAB1,
• GAB2,
• GAB3,
• Glycoprotein 130,
• Grb2,
• Growth hormone receptor,
• HoxA10,
• Insulin receptor,
• Insulin-like growth factor 1 receptor,
• IRS1,
• Janus kinase 1,
• Janus kinase 2,
• LAIR1,
• LRP1,
• PDGFRB,
• PI3K → Akt
• PLCG2,
• PTK2B,
• Ras
• SLAMF1,
• SOCS3,
• SOS1,
• STAT3,
• STAT5A, and
• STAT5B.

Further reading

• "Tie-1 Receptor Tyrosine Kinase Endodomain Interaction with SHP2: Potential Signalling Mechanisms and Roles in Angiogenesis". Angiogenesis. Advances in Experimental Medicine and Biology. 476. 2000. pp. 35–46. doi:10.1007/978-1-4615-4221-6_3. ISBN 978-1-4613-6895-3. 
• "SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone.". Recent Progress in Hormone Research 55: 293–311. 2000. PMID 11036942. 
• "Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome". Human Genetics 111 (4–5): 421–427. Oct 2002. doi:10.1007/s00439-002-0803-6. PMID 12384786. 
• "Mutations of PTPN11 are rare in adult myeloid malignancies.". Haematologica 90 (6): 853–854. Jun 2005. PMID 15951301. 
• "Germ-line and somatic PTPN11 mutations in human disease.". European Journal of Medical Genetics 48 (2): 81–96. 2005. doi:10.1016/j.ejmg.2005.03.001. PMID 16053901. 
• "PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes.". Pediatric Endocrinology Reviews 2 (4): 669–674. Jun 2005. PMID 16208280. 
• "Shp2-mediated molecular signaling in control of embryonic stem cell self-renewal and differentiation.". Cell Research 17 (1): 37–41. Jan 2007. doi:10.1038/sj.cr.7310140. PMID 17211446. 
• "How do Shp2 mutations that oppositely influence its biochemical activity result in syndromes with overlapping symptoms?". Cellular and Molecular Life Sciences 64 (13): 1585–1590. Jul 2007. doi:10.1007/s00018-007-6509-0. PMID 17453145. 

External links

• GeneReviews/NCBI/NIH/UW entry on Noonan syndrome