SHP2 (PTPN11)

SHP2, also known as PTPN11, belongs to the protein-tyrosine phosphatase(PTP) family, non-receptor class 2 subfamily. PTPs catalyze the removal of phosphate groups from tyrosine residues by the hydrolysis of phosphoric acid monoesters. They dephosphorylate EGFR, JAK2 and TYK2 kinases, promoting oncogenic transformation. SHP2 is widely expressed, with highest levels in heart, brain, and skeletal muscle. SHP2 acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. It also dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity.

SHP2 (PTPN11) Related Areas

 

SHP2 (PTPN11) Alternative Names

BPTP3, CFC, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2, PTP-2C, protein-tyrosine phosphatase 1D, protein-tyrosine phosphatase 2C, tyrosine-protein phosphatase non-receptor type 11 [Homo sapiens]

2700084A17Rik, AW536184, PTP1D, PTP2C, SAP-2, SH-PTP2, SH-PTP3, SHP-2, Shp2, Syp, SH2 domain-containing protein tyrosine phosphatase-2, protein-tyrosine phosphatase SYP, tyrosine-protein phosphatase non-receptor type 11 [Mus musculus]

Summaries for SHP2 (PTPN11)

Entrez Gene summary for PTPN11:

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:

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.

Wikipedia summary for SHP2:

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.

Human SHP2 (PTPN11) Protein General Information

 

• Protein names	SH-PTP2, Short name=Shp2
  Sequence length	597 AA.
  Domain	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.
  Catalytic activity:	Protein tyrosine phosphate + H2O = protein tyrosine + phosphate.
  Post-translational modification:	SHP2 is 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. SHP2 is phosphorylated upon activation of the receptor-type kinase FLT3. SHP2 is phosphorylated upon activation of the receptor-type kinase PDGFRA By similarity. Phosphorylated by activated PDGFRB.
  Subunit structure	SHP2 interacts with phosphorylated LIME1 and BCAR3. Interacts with SHB and INPP5D/SHIP1. SHP2 interacts with MILR1 (tyrosine-phosphorylated). SHP2 interacts with FLT1 (tyrosine-phosphorylated), FLT3 (tyrosine-phosphorylated), FLT4 (tyrosine-phosphorylated), KIT and GRB2. SHP2 interacts with PDGFRA (tyrosine phosphorylated). SHP2 interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated). Interacts with PTPNS1 and CD84. SHP2 interacts with phosphorylated SIT1 and MPZL1. SHP2 interacts with FCRL3, FCRL4, FCRL6 and ANKHD1. SHP2 interacts with KIR2DL1; the interaction is enhanced by ARRB2. Interacts with GAB2. It interacts with TERT; the interaction retains TERT in the nucleus. SHP2 interacts with PECAM1 and FER. It interacts with EPHA2 (activated); SHP2 participates in PTK2/FAK1 dephosphorylation in EPHA2 downstream signaling. SHP2 interacts with ROS1; mediates PTPN11 phosphorylation. SHP2 interacts with PDGFRB (tyrosine phosphorylated); this interaction increases the PTPN11 phosphatase activity.
  Subcellular location:	Cytoplasm.
  Tissue specificity	SHP2 is widely expressed, with highest levels in heart, brain, and skeletal muscle.
  Involvement in disease:	Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:151100]. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness. Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:163950]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. 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=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.
  Sequence similarities:	SHP2 belongs to the protein-tyrosine phosphatase family. Non-receptor class 2 subfamily. SHP2 contains 2 SH2 domains. SHP2 contains 1 tyrosine-protein phosphatase domain.

General information above from UniProt

Function for SHP2 (PTPN11) Protein

UniProtKB:

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.

Genatlas:

• 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

Homology for human SHP2 (PTPN11)

• homolog to Drosophila corkscrew
• ortholog to rattus Ptpn11
• ortholog to murine Ptpn11
• homolog to PTPN6

Phenotype Information for SHP2 (PTPN11)

• Gene/Locus: PTPN11, PTP2C, SHP2, NS1
• Phenotype: LEOPARD syndrome 1
  Leukemia, juvenile myelomonocytic
  Metachondromatosis
  Noonan syndrome 1

Phenotype Information for SHP2 from OMIM (Online Mendelian Inheritance in Man)