The protein encoded by this PTPN11 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 SHP2 protein 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 SHP2 protein 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
OMIM-Description for SHP2 / PTPN11N
The protein-tyrosine phosphatases are a highly pleomorphic set of molecules that have a role in regulating the responses of eukaryotic cells to extracellular signals (Dechert et al., 1995). They achieve this by regulating the phosphotyrosine content of specific intracellular proteins. The PTPases have been grouped by virtue of the characteristic catalytic domain sequence similarities that define this family. Dechert et al. (1995) noted that the noncatalytic domain shows a striking degree of sequence heterogeneity. In general, however, mammalian PTPases can be subdivided into 1 of 2 broad categories: (1) transmembrane receptor PTPases that contain linked cytoplasmic catalytic domains, and (2) intracellular PTPases. Included within the latter category are 2 closely related mammalian intracellular PTPases whose sequences encode 2 tandem SRC homology 2 (SH2) domains that are located at the amino-terminal side of a single PTPase catalytic domain. SH2 domains enable the binding of these SH2 domain-containing PTPases to specific phosphotyrosine residues within protein sequences. The first mammalian SH2 domain-containing PTPase identified was PTP1C (PTPN6; 176883). The second mammalian SH2 domain-containing PTPase identified is encoded by the PTPN11 gene.
SHP2 / PTPN11
Tyrosine-protein phosphatase non-receptor type 11 (PTPN11) also known as protein-tyrosine phosphatase 1D (PTP-1D) 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.
The SH2 domains repress phosphatase activity. Binding of these domains to phosphotyrosine-containing proteins relieves this auto-inhibition, possibly by inducing a conformational change in the enzyme.
Belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily. Contains 2 SH2 domains. Contains 1 tyrosine-protein phosphatase domain.
Phosphorylated on Tyr-546 and Tyr-584 upon receptor protein tyrosine kinase activation; which creates a binding site for GRB2 and other SH2-containing proteins. Phosphorylated upon activation of the receptor-type kinase FLT3. Phosphorylated upon activation of the receptor-type kinase PDGFRA (By similarity). Phosphorylated by activated PDGFRB.
Interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1 (By similarity). Interacts with MILR1 (tyrosine-phosphorylated). Interacts with FLT1 (tyrosine- phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine- phosphorylated), KIT and GRB2. Interacts with PDGFRA (tyrosine phosphorylated). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with PTPNS1 and CD84. Interacts with phosphorylated SIT1 and MPZL1. Interacts with FCRL3, FCRL4, FCRL6 and ANKHD1. Interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts with GAB2. Interacts with TERT; the interaction retains TERT in the nucleus. Interacts with PECAM1 and FER. Interacts with EPHA2 (activated); participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling. Interacts with ROS1; mediates PTPN11 phosphorylation. Interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity. Interacts with GAREM isoform 1 (tyrosine phosphorylated); the interaction increases MAPK/ERK activity and does not affect the GRB2/SOS complex formation.
Widely expressed, with highest levels in heart, brain, and skeletal muscle.
Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.
Involvement in disease
LEOPARD syndrome 1 (LEOPARD1) [MIM:151100]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. Note=The disease is caused by mutations affecting the gene represented in this entry. Noonan syndrome 1 (NS1) [MIM:163950]: A syndrome characterized by facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears. Other features can include short stature, a short neck with webbing or redundancy of skin, cardiac anomalies, deafness, motor delay and variable intellectual deficits. Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785]: An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. Note=The disease is caused by mutations affecting the gene represented in this entry. Metachondromatosis (MC) [MIM:156250]: A skeletal disorder with radiologic features of both multiple exostoses and Ollier disease, characterized by the presence of exostoses, commonly of the bones of the hands and feet, and enchondromas of the metaphyses of long bones and iliac crest. Note=The disease is caused by mutations affecting the gene represented in this entry.
SHP2 acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. SHP2 dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity.
SHP2 is involved in intracellular signal transduction in response to PDGF, EGF, insulin
SHP2 inhibites interleukin 6 signal transduction
catalytic activity required for FGF2-induced Ca2+ mobilization
SHP2 plays an essential role in IL3 signal transduction in both catalytic-dependent and -independent manners
SHP2 plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway
SHP2 is tyrosine phosphatase which functions as a positive regulator downstream of RTKs, activating growth-stimulatory signalling pathways
SHP2 plays an essential role in normal hematopoiesis and inducing aberrant hyperactivation of the Ras-Erk pathway
SHP2 modulates and regulates signaling through numerous pathways, many of which are active in the developing endocardial cushions and implicated the ERK pathway as a central mechanism
SHP2 mediates dephosphorylation of ROCK2 and, therefore, regulates RhoA-induced cell rounding, indicating that it couples with RhoA signaling to control ROCK2 activation during deadhesion
SHP2 has a role in adhesion-dependent activation of the RhoA family small GTPases
SHP2 promotes HER2-induced signaling and transformation at least in part by dephosphorylating a negative regulatory autophosphorylation site
SHP2 regulates tyrosine phosphorylation of NEDD9, hence opposing the effect of kinases, and is a negative regulator of cell migration mediated by NEDD9
SHP2 is involved in the SEMA4D-signaling in the developing nervous system
SHP2 regulates myogenesis by coupling to PTK2 signaling pathway
PTPN11-mediated Ras-mitogen-activated protein kinase (Ras-MAPK) signaling plays a critical role in Müller cell maturation and function, which is necessary for the survival of retinal neurons
SHP2 plays a role in controlling Ras signaling, and retinal degeneration caused by aberrant receptor tyrosine kinase (RTK)-Shp2 signaling may be prevented by direct intervention in the Ras-MAPK pathway
SHP2's signaling may play equally important roles in retinal survival in both physiological and pathological conditions
SHP2 governs the opposing functions of parafibromin, deregulation of which may cause the development of tumors or developmental malformations)
SHP2 plays an important role in STAT5 activation and growth factor -mediated proliferation, survival, and differentiation of human progenitor cells
SHP2 is required for induction of CEBPA expression and granulopoiesis in response to CSF3 or other cytokines independent of PTPN11-mediated ERK activation