Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known asprotein-tyrosine phosphatase 1D (PTP-1D),Src homology region 2 domain-containing phosphatase-2 (SHP-2), orprotein-tyrosine phosphatase 2C (PTP-2C) is anenzyme that in humans is encoded by thePTPN11gene. PTPN11 is aprotein tyrosine phosphatase (PTP) Shp2.[5][6]
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, andoncogenic 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 ofNoonan syndrome as well asacute myeloid leukemia.[7]
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).[8] In zebrafish, SHP-2 and SHP-2L have overlapping functional abilities.[9] SHP-2 and SHP-2L are quite distinct from SHP-1 (PTPN6).[8]
PTPN11 encodes theprotein tyrosine phosphatase SHP2, which has a modular structure essential for its regulatory function in cell signaling. SHP2 consists of two tandemSrc homology 2 (SH2) domains at theN-terminus (N-SH2 and C-SH2), followed by a catalytic protein tyrosine phosphatase (PTP) domain and a C-terminal tail containing tyrosyl phosphorylation sites.[10][11] In its inactive, auto-inhibited conformation, the N-SH2 domain binds intramolecularly to the PTP catalytic domain, blocking substrate access to the active site.[12][11] Upon binding tophosphotyrosyl residues on target proteins, the N-SH2 domain undergoes a conformational change that releases the PTP domain, thereby activating the enzyme.[12][10][11] 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.[12] This structural arrangement allows SHP2 to tightly regulate signaling pathways by selectivelydephosphorylating substrates involved in cell growth, differentiation, and migration.[10] Mutations disrupting the interface between the N-SH2 and PTP domains can lead to constitutive activation or impairment of SHP2, underlying diseases such asNoonan syndrome and certainleukemias.[13][10] 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.[12][11][10]
PTPN11 encodes SHP2, a ubiquitously expressed protein tyrosine phosphatase that plays an important role in regulatingcell signaling pathways, most notably theRAS/MAPK cascade, which controlscell 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 ofgrowth factor andcytokine signals.[12] Duringembryonic development, SHP2 is essential for the formation of the heart, blood cells, bones, and other tissues.[13]Germline mutations in PTPN11 cause developmental disorders such asNoonan syndrome andLEOPARD syndrome, while somatic mutations are frequently implicated inhematologic malignancies andsolid tumors by promoting aberrant activation of oncogenic pathways.[14][15] In cancer, SHP2 can function as an oncogenic driver by sustaining RAS/RAF/MAPK signaling and supporting tumor cell growth and survival.[16] Thus, PTPN11/SHP2 is a critical regulator of both normal cellular processes and disease states, with its dysregulation contributing to developmental syndromes andoncogenesis.
Missense mutations in the PTPN11 locus are associated with bothNoonan syndrome andLeopard syndrome. At least 79 disease-causing mutations in this gene have been discovered.[17]
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.[18] 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.[19]
The mutations that cause Leopard syndrome are restricted regions affecting the catalytic core of the enzyme producing catalytically impaired Shp2 variants.[20][21] It is currently unclear how mutations that give rise to mutant variants of Shp2 with biochemically opposite characteristics result in similar human genetic syndromes.
CagA is a protein andvirulence factor inserted byHelicobacter 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 inapoptosis of the host cell. Epidemiological studies have shown roles of cagA- positiveH. pylori in the development ofatrophic gastritis,peptic ulcer disease andgastric carcinoma.[27]
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^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
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^abTartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. (December 2001). "Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome".Nature Genetics.29 (4):465–468.doi:10.1038/ng772.PMID11704759.
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^Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, et al. (October 1997). "Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells".Biochemical and Biophysical Research Communications.239 (2):412–417.Bibcode:1997BBRC..239..412C.doi:10.1006/bbrc.1997.7480.PMID9344843.
^Guo W, Xu Q. Phosphatase-independent functions of SHP2 and its regulation by small molecule compounds.J Pharmacol Sci. 2020 Nov;144(3):139-146.doi:10.1016/j.jphs.2020.06.002PMID32921395
^Kang D, Wang Y, Lin Y, Ma WW, Morgensztern D, Leventakos K, Bi C, Ding Y, Xiong J, Yan M, Sun X, Wang P, Ma C, Wang Y. JAB-3312, a Potent Allosteric SHP2 Inhibitor That Enhances the Efficacy of RTK/RAS/MAPK and PD-1 Blockade Therapies.Clin Cancer Res. 2025 Jul 15;31(14):3019-3032.doi:10.1158/1078-0432.CCR-24-3691PMID40333694
^Luo J, Villaruz LC. Combined SHP2 and KRASG12C inhibitor therapy in patients with non-small-cell lung cancer.Lancet Respir Med. 2025 Nov 28:S2213-2600(25)00298-X.doi:10.1016/S2213-2600(25)00298-XPMID41325754
^Song H, Zou X, Liang J, Huang H, Liu Y, Zhang Y, Liu Y, Chen L, Li H. Discovery of SA-8 as a potent SHP2-AUTAC degrader in cancer therapy.Eur J Med Chem. 2025 Nov 5;297:117918.doi:10.1016/j.ejmech.2025.117918PMID40609222
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