Affinage

Showing PTPN11 — SHP2 is a alias.

PTPN11

Tyrosine-protein phosphatase non-receptor type 11 · UniProt Q06124

Length
593 aa
Mass
68.0 kDa
Annotated
2026-06-10
100 papers in source corpus 53 papers cited in narrative 53 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHP-2 (PTPN11) is a cytoplasmic protein tyrosine phosphatase that serves as a central positive amplifier of receptor tyrosine kinase and cytokine signaling toward the RAS/MAPK and PI3K/AKT pathways, while acting as a negative regulator of several inhibitory and inflammatory circuits (PMID:8514779, PMID:11593409, PMID:29514104). Its activity is governed by a conformational switch: disease-associated Noonan-syndrome mutations cluster at the interacting N-SH2/PTP interface and shift the equilibrium toward the active open state, whereas LEOPARD-syndrome mutations abolish catalytic activity, mechanisms confirmed by crystallography of wild-type and mutant proteins (PMID:11704759, PMID:24628801). Physiologically, the SH2 domains engage phosphotyrosine ligands—growth-factor receptors, docking proteins such as GAB1 and FRS-2, and inhibitory receptor ITSMs such as PD-1—to relieve autoinhibition and stimulate catalysis; PD-1 engagement bridges two receptor tails through both SH2 domains to robustly activate the enzyme (PMID:14974085, PMID:32184441, PMID:17928416, PMID:12370245). SHP-2 promotes RAS activation upstream of SOS and drives sustained ERK signaling downstream of EGF, PDGF, FGF, and insulin, paradoxically enhancing MAPK output even while dephosphorylating receptors such as PDGFR (PMID:9931295, PMID:12370245, PMID:10671568, PMID:29514104), and it supports PI3K/AKT/mTOR signaling required for survival, cell size control, and tumorigenesis (PMID:11593409, PMID:21393858, PMID:22058153). Direct substrates include p190-B RhoGAP (linking SHP-2 to RhoA activation and myogenesis), STAT5A, IRS-1, and PDGFR, and unbiased phosphoproteomics establishes SHP-2 as a master regulator of the PDGFR phosphotyrosine network controlling targets including RASA1, cortactin, and GAB1 (PMID:7515062, PMID:12615921, PMID:15169898, PMID:29514104). As a negative regulator it dampens JAK/STAT signaling, restrains TRIF-dependent TLR/TBK1 responses via a phosphatase-independent C-terminal interaction with TBK1, and limits Schwann cell, T-cell, NK-cell, osteoclast, and myeloid responses (PMID:10022928, PMID:17157040, PMID:19805360, PMID:15933714, PMID:30926899, PMID:25593124, PMID:36581713). SHP-2 is essential for hematopoietic and lymphoid development, cell spreading and migration through FAK/Src, and convergence-extension movements during gastrulation via Src-family kinases and RhoA (PMID:9694867, PMID:11159516, PMID:18159945). Its activity is itself tuned by oxidative and nitrosative modification of the active-site cysteine and by Abl-mediated phosphorylation feedback (PMID:23382182, PMID:15933714, PMID:18827006). PTPN11 mutations cause Noonan syndrome and LEOPARD-syndrome/hypertrophic cardiomyopathy and underlie somatic transformation in juvenile myelomonocytic leukemia and KRAS-driven solid tumors (PMID:11704759, PMID:22058153, PMID:14644997, PMID:29808009).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1993 High

    Established that SHP-2 is physically coupled to activated growth factor receptors, providing the first link between the phosphatase and RTK signaling.

    Evidence Co-IP and SH2 direct-binding assays showing SH-PTP2 binds activated EGFR/PDGFR via its N-SH2 domain and is itself tyrosine-phosphorylated

    PMID:8514779

    Open questions at the time
    • Did not determine functional consequence of receptor binding
    • Substrates downstream of receptor recruitment not identified
  2. 1994 High

    Showed SHP-2 actively dephosphorylates a defined substrate (IRS-1) and that its SH2 domains allosterically enhance catalysis, foreshadowing the autoinhibition model.

    Evidence In vitro phosphatase assay comparing full-length versus SH2-deleted enzyme on pY-IRS-1

    PMID:7515062

    Open questions at the time
    • Structural basis of SH2-mediated activation not resolved
    • Physiological relevance of IRS-1 dephosphorylation not tested in vivo
  3. 1999 High

    Resolved that SHP-2 has opposing roles on different pathways—positively engaging ERK while negatively regulating JAK/STAT.

    Evidence gp130 Y118F receptor mutant in ES cells, MEK inhibitor, and Shp-2-deficient fibroblasts with elevated STAT1 phosphorylation rescued by WT re-expression

    PMID:10022928 PMID:10364425

    Open questions at the time
    • Direct STAT substrate dephosphorylation not biochemically demonstrated here
    • Mechanism of ERK activation versus receptor dephosphorylation paradox unresolved
  4. 1998 High

    Defined the domain requirements for SHP-2 function and placed it in cell adhesion/cytoskeletal control via FAK and Src.

    Evidence Xenopus mesoderm induction with domain-deletion/chimera mutants; Shp-2 mutant fibroblasts with impaired spreading and reduced FAK dephosphorylation

    PMID:9418864 PMID:9694867

    Open questions at the time
    • Direct FAK substrate relationship not established by substrate trapping
    • PTP-domain specificity determinants only partially mapped
  5. 2000 Medium

    Placed SHP-2 epistatically upstream of RAS and RhoA, defining its dual control of MAPK and small-GTPase signaling.

    Evidence Catalytically inactive SHP-2 blocking insulin/EGF Ras activation upstream of SOS; genetic and calpeptin perturbation elevating active RhoA

    PMID:10671568 PMID:11114521

    Open questions at the time
    • Direct RhoA-pathway substrate not yet identified in these studies
    • Mechanism linking phosphatase activity to RAS-GTP loading unresolved
  6. 2001 High

    Identified PTPN11 gain-of-function mutations as the cause of Noonan syndrome, linking conformational activation to human disease.

    Evidence Mutation screening plus energetics-based structural analysis of N-SH2 mutants showing equilibrium shift to active state

    PMID:11704759

    Open questions at the time
    • Direct measurement of mutant phosphatase activity not in this study
    • Downstream effector dysregulation not yet defined
  7. 2001 High

    Demonstrated SHP-2 as a target hijacked by a bacterial effector and required for PI3K/AKT and hematopoietic development.

    Evidence CagA complex formation activating SHP-2; SH2-domain-dependent PI3K p85 co-IP and Akt activation; RAG-2 blastocyst complementation showing no lymphoid development in Shp-2-null cells

    PMID:11159516 PMID:11593409 PMID:11743164

    Open questions at the time
    • Precise mechanism by which SHP-2 promotes PI3K recruitment not fully defined
    • Relevant hematopoietic substrates not identified
  8. 2002 High

    Established GAB1/FRS-2 docking-protein recruitment as the route by which SHP-2 drives RAS activation and controls cell fate.

    Evidence Gab1(Y627F) and SHP-2(C459S) reducing active Ras with Ras rescue; FGF-induced SHP-2/FRS-2α complex required for ERK activation in myoblasts

    PMID:11997521 PMID:12370245

    Open questions at the time
    • Direct substrate dephosphorylated to enable Ras activation not pinpointed
    • Erk-independent repression of myogenesis mechanistically unresolved
  9. 2003 Medium

    Identified STAT5A as a direct SHP-2 substrate and tied somatic PTPN11 mutations to leukemia through RAS.

    Evidence pY-Stat5A affinity purification and dephosphorylation kinetics in Shp-2-deficient cells; JMML mutation screening mutually exclusive with RAS/NF1 plus Ba/F3 growth-factor-independence

    PMID:12615921 PMID:14644997

    Open questions at the time
    • JMML study showed negative ERK/Akt hyperactivation, leaving effector mechanism open
    • Leukemogenic substrate spectrum not defined
  10. 2004 High

    Connected SHP-2 conformational activation in disease mutants to sustained GAB1 binding and ERK output, and identified p190-B RhoGAP as a direct substrate linking SHP-2 to RhoA-dependent myogenesis.

    Evidence Noonan mutant phosphatase assays with GAB1-FF dominant negative; substrate-trapping mutants identifying p190-B RhoGAP with RhoA activity readout

    PMID:14974085 PMID:15169898

    Open questions at the time
    • How dephosphorylation of a RhoGAP activates rather than inhibits RhoA mechanistically incomplete
    • Generalizability of GAB1-sustained ERK to all mutants untested
  11. 2005 Medium

    Revealed redox control of SHP-2 and context-dependent negative regulation of neurotrophin and TCR signaling.

    Evidence TCR-induced ROS oxidation of active-site cysteine with LAT/Gads/SLP-76 recruitment; Ca2+-enhanced SHP-2/TrkB association inhibiting BDNF signaling reversed by Shp2 deletion

    PMID:15650750 PMID:15933714

    Open questions at the time
    • Single-lab redox findings without independent confirmation
    • Direct TrkB dephosphorylation versus indirect inhibition not distinguished
  12. 2006 High

    Defined phosphatase-independent functions of SHP-2 as a scaffold/chaperone, restraining innate immune TLR/TBK1 signaling and stabilizing Bcr-Abl.

    Evidence C-terminal domain binding to TBK1 with SHP-2-deficient cytokine analysis; Hsp90 co-IP and proteasome-dependent p210 Bcr-Abl degradation upon SHP-2 loss

    PMID:17003374 PMID:17157040

    Open questions at the time
    • Structural basis of non-catalytic TBK1/Hsp90 interactions not defined
    • Balance between catalytic and scaffold roles in leukemia not quantified
  13. 2007 High

    Placed SHP-2 in cardiac progenitor maintenance and gastrulation movements through FGF/FRS-2, Src-family kinases, and RhoA.

    Evidence Xenopus cardiac progenitor assays with FRS-2 co-IP and FGF rescue; zebrafish morpholino knockdown rescued by active Fyn/Yes/RhoA, with patient mutants causing convergence-extension defects

    PMID:17928416 PMID:18159945

    Open questions at the time
    • Direct substrates mediating C&E movements not identified
    • How both GOF and LOF mutants converge on the same defect mechanistically unresolved
  14. 2011 High

    Established tissue-specific roles of SHP-2 spanning tumor suppression, Schwann cell ErbB signaling, and mTOR-driven cardiomyopathy.

    Evidence Hepatocyte Shp2/Stat3 double KO abolishing HCC; conditional Schwann-cell KO with Src-inhibitor phenocopy; PDGFRα glioma model with PI3K rescue; cardiomyocyte Q510E transgenic rescued by rapamycin

    PMID:19805360 PMID:21393858 PMID:21575863 PMID:22058153

    Open questions at the time
    • Context-dependent tumor suppressor versus oncogenic roles not mechanistically unified
    • Direct substrates in each tissue largely undefined
  15. 2012 Medium

    Extended SHP-2 function to actin/ROCK control of cardiac development, osteoclast fusion, and nutrient-sensing mTOR signaling.

    Evidence Xenopus Noonan mutant cardiac defects rescued by ROCK inhibition; osteoclast-specific KO osteopetrosis with RANKL/Nfatc1 defect; myoblast leucine-induced S6K1 activation via PLCβ4/Ca2+

    PMID:22278918 PMID:23129808 PMID:25593124

    Open questions at the time
    • Direct substrate connecting SHP-2 to ROCK and Ca2+ pathways not identified
    • Leucine-sensing mechanism is single-lab
  16. 2013 Medium

    Broadened SHP-2 into vascular, endothelial, and intestinal barrier regulation and revealed negative-feedback loops controlling its recruitment.

    Evidence S-nitrosylation inhibiting neuronal SHP-2/ERK; ICAM-1/VE-cadherin interactions in endothelium; IEC-specific KO causing microbiota-dependent colitis; RSK phosphorylation of Gab2 limiting SHP-2 recruitment

    PMID:23382182 PMID:23401857 PMID:23530062 PMID:28701303

    Open questions at the time
    • Several endothelial/feedback findings are single-lab
    • Direct substrates in barrier regulation not mapped
  17. 2014 High

    Provided direct structural evidence distinguishing Noonan (activating) from LEOPARD (inactivating) mutations.

    Evidence X-ray crystallography of wild-type and five disease-mutant SHP2 proteins

    PMID:24628801

    Open questions at the time
    • Dynamics of the autoinhibitory switch not captured by static structures
    • Allosteric ligand-binding states not resolved here
  18. 2016 High

    Uncovered a cell-cycle role for SHP-2 at mitotic structures, linking GOF mutations to chromosomal instability via Plk1/c-Src.

    Evidence Immunofluorescence localization to kinetochore/centrosome/midbody and Plk1/c-Src kinase assays in Ptpn11 GOF knock-in MEFs

    PMID:26755576

    Open questions at the time
    • Direct mitotic substrate of SHP-2 not identified
    • Single-study mitotic localization needs independent confirmation
  19. 2018 High

    Defined SHP-2 as a master regulator of the PDGFR phosphoproteome and a druggable node for KRAS-driven cancer, with a second allosteric site for inhibition.

    Evidence Quantitative phosphoproteomics with allosteric inhibitor SHP099; genetic Ptpn11 deletion in KRAS PDAC/NSCLC models with MEK-inhibitor synergy; crystallography of a second allosteric SHP244 site

    PMID:29304282 PMID:29514104 PMID:29808009

    Open questions at the time
    • Direct versus indirect substrates within the phosphoproteome not fully separated
    • Resistance mechanisms to dual SHP2/MEK inhibition incompletely defined
  20. 2019 Medium

    Tied SHP-2 to immune-cell metabolism and inflammatory vascular dysfunction.

    Evidence NK-cell-specific KO with ERK and Seahorse metabolic defects; sepsis model showing ROS-inactivated SHP-2 interacting with MyD88 via Y257

    PMID:30905847 PMID:30926899

    Open questions at the time
    • MyD88 interaction is single-lab via proximity ligation
    • Metabolic regulation mechanism downstream of ERK not detailed
  21. 2020 High

    Provided the biophysical basis for SHP-2 activation by inhibitory immune receptors through dual-ITSM bridging of PD-1.

    Evidence ITC, live-cell PD-1 dimerization, and enzymatic activation assays showing both SH2 domains engage two pY-ITSM-Y248 tails

    PMID:32184441

    Open questions at the time
    • Downstream substrates dephosphorylated upon PD-1 engagement not defined here
    • Stoichiometry in physiological synapses not established
  22. 2022 High

    Connected the PD-1/SHP-2 module to myeloid differentiation and tumor immunity beyond T cells.

    Evidence Myeloid-specific SHP-2 or PD-1 KO with PD-1–SHP-2 recruitment to GM-CSF receptor and HOXA10/IRF8 phosphorylation analysis

    PMID:36581713

    Open questions at the time
    • Whether HOXA10/IRF8 are direct SHP-2 substrates not established
    • Catalytic versus scaffold contribution to myeloid effect not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHP-2's small set of validated direct substrates accounts for its simultaneous positive (RAS/MAPK, PI3K) and negative (JAK/STAT, RhoA, TLR) outputs across tissues remains the central unresolved question.
  • Few direct catalytic substrates identified relative to breadth of phenotypes
  • Tissue-specific substrate selection mechanism unknown
  • Integration of catalytic and scaffold/chaperone functions not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 4 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005829 cytosol 3 GO:0005856 cytoskeleton 2 GO:0005739 mitochondrion 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 5 R-HSA-1640170 Cell Cycle 1 R-HSA-5357801 Programmed Cell Death 1
Partners
FRS-2GAB1GRB2JAK2PD-1PDGFRSTAT5ATBK1
Complex memberships
LAT-Gads-SLP-76 complexPD-1:PD-1 dimer

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Missense mutations in PTPN11 (encoding SHP-2) cause Noonan syndrome. All mutations cluster in interacting portions of the N-SH2 domain and the phosphotyrosine phosphatase (PTP) domain involved in switching the protein between inactive and active conformations. Energetics-based structural analysis of two N-SH2 mutants indicates a significant shift of equilibrium favoring the active conformation, implying gain-of-function changes with excessive SHP-2 activity. Mutational analysis, energetics-based structural analysis of N-SH2 domain mutants Nature genetics High 11704759
2001 H. pylori CagA protein is injected into host cells, undergoes tyrosine phosphorylation, and forms a physical complex with SHP-2 in a phosphorylation-dependent manner, stimulating SHP-2 phosphatase activity. Disruption of the CagA-SHP-2 complex abolished CagA-dependent cellular (growth factor-like) response, and the CagA effect was reproduced by constitutively active SHP-2. Co-immunoprecipitation, phosphatase activity assay, dominant-active SHP-2 expression, disruption of complex Science High 11743164
1999 SHP-2 and ERK signaling downstream of gp130 suppresses mouse ES cell self-renewal. A gp130 receptor mutant (Y118F) that fails to engage SHP-2 and cannot activate ERKs supports ES cell self-renewal at 100-fold lower cytokine concentrations with sustained STAT3 activation. MEK inhibitor PD098059 also enhanced undifferentiated ES cell growth, indicating that ERK activation actively impairs self-renewal. Chimeric receptor mutagenesis (Y118F), MEK inhibitor (PD098059), ES cell self-renewal assay, STAT3 activation measurement Developmental biology High 10364425
1998 Shp-2 is required for cell spreading, migration, and regulation of focal adhesion architecture. Fibroblasts lacking functional Shp-2 show impaired spreading and migration on fibronectin, increased focal adhesions, and condensed F-actin. FAK dephosphorylation was significantly reduced in Shp-2 mutant cells in suspension, and regulated association of Src SH2 domain with FAK and paxillin during cell attachment/detachment on fibronectin was disrupted. Genetic knockout (Shp-2 mutant fibroblasts), fibronectin adhesion/migration assays, biochemical analysis of FAK phosphorylation, Src-FAK-paxillin co-IP The Journal of biological chemistry High 9694867
1999 Shp-2 functions as a negative regulator of the interferon-stimulated JAK/STAT pathway. Shp-2-deficient fibroblasts show augmented suppression of cell viability and markedly elevated STAT1 tyrosine phosphorylation and DNA binding upon IFN-α or IFN-γ stimulation. Reintroduction of wild-type Shp-2 reversed hypersensitivity to IFNs and excessive STAT activation. Shp-2 knockout fibroblasts, EMSA (hSIE probe), Western blot for STAT1 phosphorylation, rescue with wild-type Shp-2 re-expression Molecular and cellular biology High 10022928
2003 Somatic PTPN11 mutations occur in juvenile myelomonocytic leukemia (JMML) and are largely mutually exclusive with RAS and NF1 mutations, suggesting mutant SHP-2 proteins deregulate myeloid growth through Ras. Ba/F3 cells expressing leukemia-associated SHP-2 proteins showed enhanced growth factor-independent survival. Mutation screening, Ba/F3 cell growth factor-independence assay, biochemical analysis of ERK/Akt Blood Medium 14644997
2004 Noonan syndrome-associated SHP-2/PTPN11 mutants have increased basal phosphatase activity and, after EGF stimulation, show prolonged binding to GAB1 and sustained ERK2/MAPK1 activation. Coexpression of GAB1-FF (lacking SHP-2 binding motifs) blocked EGF-mediated increase in SHP-2 phosphatase activity and dramatically reduced ERK2 activation. Phosphatase activity assays, co-immunoprecipitation of GAB1-SHP-2, ERK2 activation (Western blot), GAB1-FF dominant-negative expression Human mutation High 14974085
2011 Hepatocyte-specific deletion of Shp2 promotes inflammatory signaling through the Stat3 pathway, leading to hepatic inflammation/necrosis, regenerative hyperplasia, and tumor development in aged mice. Concurrent deletion of Shp2 and Stat3 abolished DEN-induced hepatocellular carcinoma, establishing a Stat3-dependent tumor-suppressor function for Shp2 in liver. Hepatocyte-specific conditional knockout (Cre-lox), genetic epistasis (double Shp2/Stat3 KO), DEN-induced HCC model Cancer cell High 21575863
1993 SH-PTP2 (SHP-2) associates in vivo with ligand-activated EGF and PDGF receptors via its N-terminal SH2 domain. SH-PTP2 itself becomes tyrosyl phosphorylated upon growth factor activation. Co-immunoprecipitation from cells, SH2 domain direct binding assay, phosphotyrosine Western blot The Journal of biological chemistry High 8514779
1994 PTP2C (SHP-2) rapidly dephosphorylates tyrosine-phosphorylated IRS-1. The SH2 domains of PTP2C enhance its activity toward IRS-1 (dephosphorylation by the SH2 domain-deleted form was ~3-fold slower), suggesting that SH2-domain binding to pY-IRS-1 allosterically activates the phosphatase toward this substrate. In vitro phosphatase assay with recombinant IRS-1 and truncated PTP2C, comparison of full-length vs. SH2-deleted enzyme The Journal of biological chemistry High 7515062
1997 SHP-2 is tyrosine-phosphorylated by JAK1 and JAK2 (but not JAK3) and associates with them. The SH2 domains of SHP-2 are not essential for JAK binding; instead, amino acids 232–272 in SHP-2 mediate the interaction. JAKs phosphorylate SHP-2 on Y304 and Y327, and phosphorylated SHP-2 associates with the adaptor Grb2. The N-terminus of JAK2 (not its kinase-like domain) is required for association with SHP-2. COS-1 cell co-transfection, co-immunoprecipitation, domain-deletion/point-mutation mapping, kinase assay The Journal of biological chemistry High 8995399
2000 Shp-2 acts upstream of RhoA to regulate its activity. Perturbation of Shp-2 activity by genetic manipulations (including catalytically inactive mutants and deletion) results in raised levels of active RhoA. Calpeptin, which interferes with Shp-2 catalytic activity in vitro, also elevates active RhoA in vivo. Genetic manipulation of Shp-2 (dominant negative and null), RhoA activity assay (GTP-loading), in vitro calpeptin inhibition of Shp-2 Current biology High 11114521
2001 SHP-2 is required for mediating PI3K/Akt activation by growth factors (EGF, PDGF, IGF). Deletion of the N-terminal SH2 domain of SHP-2 severely impaired PDGF- and IGF-induced Akt phosphorylation. EGF stimulation induced co-immunoprecipitation of the p85 subunit of PI3K with SHP-2. Ectopic wild-type SHP-2 expression elevated EGF-induced Akt phosphorylation in an N-terminal SH2-domain-dependent manner. SHP-2 domain-deletion (exon 3) cell lines, co-immunoprecipitation of PI3K p85 with SHP-2, Akt phosphorylation (Western blot), lipid kinase assay, reconstitution in SHP-2-/- fibroblasts Oncogene High 11593409
2003 Shp-2 is a Stat5A phosphatase. Shp-2 (but not Shp-1) specifically interacted with tyrosine-phosphorylated Stat5A in vivo. Shp-2 accelerated Stat5A dephosphorylation, and dephosphorylation of Stat5A was dramatically delayed in Shp-2-deficient cells. Affinity purification using pY-Stat5A peptides, co-immunoprecipitation, dephosphorylation kinetics assay, Shp-2-deficient cell comparison The Journal of biological chemistry High 12615921
1998 Both SH2 domains and the PTP catalytic domain of SHP-2 are required for normal function in Xenopus mesoderm induction. The N-terminal SH2 domain is absolutely required, the C-terminal SH2 contributes to wild-type function, whereas C-terminal tyrosyl phosphorylation sites and proline-rich region are dispensable. SHP-2/SHP-1 chimera studies revealed that substantial specificity resides in the PTP domain itself. Xenopus mesoderm induction assay, domain-deletion and chimera mutagenesis (SHP-2/SHP-1 chimeras), functional readout (mesoderm induction, gastrulation) Molecular and cellular biology High 9418864
2004 SHP-2 positively regulates myogenesis by dephosphorylating p190-B RhoGAP, which promotes RhoA activation. SHP-2 substrate-trapping mutants identified p190-B RhoGAP as a direct SHP-2 substrate. During myogenesis, p190-B RhoGAP tyrosyl dephosphorylation correlated with SHP-2 phosphatase activation; a catalytically inactive SHP-2 mutant inhibited p190-B RhoGAP dephosphorylation, RhoA activity, and myogenesis. SHP-2 substrate-trapping mutants, co-immunoprecipitation, RhoA activity assay, catalytically inactive SHP-2 overexpression, RNAi knockdown Molecular and cellular biology High 15169898
1999 SHP-2 dephosphorylates the PDGF receptor, yet enhances PDGF-induced MAP kinase pathway activation. Catalytically active SHP-2 decreased PDGF receptor tyrosine phosphorylation while enhancing MAP kinase activation; catalytically inactive SHP-2 had the opposite effects. Co-expression of active/inactive SHP-2 with PDGF receptor in HEK293 cells, receptor phosphorylation assay, MAP kinase activation assay The Biochemical journal Medium 9931295
2006 Gain-of-function SHP-2 mutants (Noonan syndrome-associated) enhance FGF-2-mediated Ca2+ oscillations in fibroblasts and spontaneous Ca2+ oscillations in cardiomyocytes. Enhanced Ca2+ oscillation frequency correlates with reduced nuclear translocation and transcriptional activity of NFAT, dependent on SHP-2 phosphatase activity. Ca2+ oscillation imaging, NFAT nuclear translocation assay, gain-of-function SHP-2 mutant expression in fibroblasts and cardiomyocytes Proceedings of the National Academy of Sciences of the United States of America Medium 16461457
2009 Shp-2 is an essential component of Neuregulin-1/ErbB signaling in Schwann cells. Conditional mutation of Shp2 in neural crest cells/Schwann cells abolished Nrg1-evoked proliferation and migration and altered Nrg1-dependent intracellular signaling. Pharmacological inhibition of Src family kinases mimicked all effects, implicating Src as a primary Shp-2 target during Nrg1 signaling. Conditional knockout (neural crest/Schwann cell-specific), Schwann cell proliferation/migration assays, Src family kinase inhibitor phenocopy Proceedings of the National Academy of Sciences of the United States of America High 19805360
1997 SHP-2 (but not SHP-1) associates with tyrosine-phosphorylated PECAM-1 (CD31) via its SH2 domains following integrin or immune receptor activation. SHP-2 SH2 domain fusion protein directly bound phosphorylated PECAM-1, and SHP-2 dephosphorylated PECAM-1 in immune precipitate phosphatase assays. Co-immunoprecipitation, SH2 domain GST-pulldown, direct binding to pY-PECAM-1, immune-complex phosphatase assay The Journal of biological chemistry Medium 9388260
2005 TCR activation induces ROS-dependent transient inactivation (oxidation) of SHP-2's active site cysteine. SHP-2 is recruited to the LAT-Gads-SLP-76 complex and directly regulates phosphorylation of Vav1 and ADAP. ADAP association with SLP-76 is regulated by SHP-2 in a redox-dependent manner, promoting T-cell adhesion through integrin activation. Oxidation assay of active-site cysteine, co-immunoprecipitation with LAT/Gads/SLP-76 complex, phosphorylation analysis of Vav1/ADAP, T-cell adhesion assay The EMBO journal Medium 15933714
2006 SHP-2 negatively regulates TRIF-dependent TLR signaling by directly binding TANK-binding kinase 1 (TBK1) via its C-terminal domain (interaction with TBK1 kinase domain), independent of phosphatase activity. SHP-2 deficiency increased TBK1-activated IFN-β and TNF-α expression. SHP-2 also inhibited poly(I:C)-induced MAP kinase pathway activation. Co-immunoprecipitation of SHP-2 C-terminal domain with TBK1, SHP-2-deficient cell analysis, TBK1 knockdown epistasis, cytokine measurement Immunity High 17157040
2011 SHP-2 (PTPN11) is required for PDGFRA-driven gliomagenesis in Ink4a/Arf-deficient cells. Abrogation of SHP-2-binding motifs in PDGFRα or SHP-2 shRNA knockdown disrupted PI3K interaction with PDGFRα, suppressed AKT/mTOR activation, and impaired tumorigenesis. Activated PI3K mutant expression rescued the effect of SHP-2 inhibition, placing SHP-2 upstream of PI3K in this pathway. Receptor mutagenesis (SHP-2 binding site ablation), shRNA knockdown, pharmacological SHP-2 inhibition, activated PI3K rescue, in vivo glioma model The Journal of clinical investigation High 21393858
2013 S-nitrosylation of SHP-2 at its active-site cysteine by NO (forming SNO-SHP-2) inhibits its phosphatase activity in neurons. NMDA exposure and transient focal cerebral ischemia increased SNO-SHP-2 levels, blocking downstream ERK1/2 neuroprotective signaling and increasing susceptibility to NMDA receptor-mediated excitotoxicity. S-nitrosylation assay (biotin-switch), phosphatase activity assay of SNO-SHP-2, NMDA treatment in vitro, focal ischemia model in vivo, ERK1/2 activation assay Proceedings of the National Academy of Sciences of the United States of America High 23382182
2005 Tyrosine phosphatase SHP-2 negatively regulates TrkB receptor activity in cerebellar neurons under conditions of excessive calcium influx. Calcium influx (via L-type channels or glutamate receptors) enhanced association of Shp-2 with TrkB receptors, inhibiting BDNF-induced TrkB autophosphorylation and downstream Ras/Erk/Akt activation. Deletion of the Shp2 gene reversed inhibition of TrkB and increased neuronal survival. Shp-2 gene deletion in neuronal cultures, co-immunoprecipitation of Shp-2 with TrkB, TrkB autophosphorylation assay, neuronal survival assay with depolarization/glutamate The EMBO journal High 15650750
2008 SHP-2 is a novel substrate of Abl family kinases during growth factor-mediated proliferation. Endogenous Abl kinases phosphorylate SHP-2 on Y580, inducing sustained ERK activation. Abl kinases also indirectly mediate phosphorylation of SHP-2 on Y63 and Y279; phosphorylation of Y279 downregulates sustained ERK activation and proliferation, constituting a negative-feedback mechanism. Pharmacological Abl inhibition (imatinib), RNAi knockdown, site-directed mutagenesis of SHP-2 phosphorylation sites, ERK activation assay, proliferation (G1-to-S) assay Journal of cell science Medium 18827006
2006 SHP-2 is required for hematopoietic cell transformation by Bcr-Abl. SHP-2 interacts with Hsp90, and loss of SHP-2 leads to proteasome-mediated degradation of p210 Bcr-Abl independently of SHP-2's catalytic activity. Inhibition of SHP-2 enzymatic activity (without destabilizing p210) also enhanced apoptosis, indicating a dual role (chaperone and signaling) of SHP-2 in Bcr-Abl leukemogenesis. Shp-2 conditional deletion in hematopoietic cells, leukemia transplantation model, Hsp90 co-immunoprecipitation, proteasome inhibitor rescue, antisense/siRNA knockdown, catalytically inactive SHP-2 overexpression Blood High 17003374
2016 Gain-of-function Ptpn11 mutations disturb mitosis and cytokinesis, causing chromosomal instability. Shp-2 localizes to the kinetochore, centrosome, spindle midzone, and midbody. GOF mutant Shp-2 hyperactivates Polo-like kinase 1 (Plk1) by enhancing c-Src kinase-mediated tyrosine phosphorylation of Plk1. Immunofluorescence localization of Shp-2 to mitotic structures, Plk1 kinase assay, c-Src kinase assay, MEFs from Ptpn11 GOF knock-in mice, chromosomal instability analysis Proceedings of the National Academy of Sciences of the United States of America High 26755576
2020 SHP-2 bridges two PD-1 molecules by simultaneously engaging phosphorylated ITSM-Y248 residues on two PD-1 cytoplasmic tails via its N-SH2 and C-SH2 domains, forming a PD-1:PD-1 dimer. This dual engagement induces robust SHP-2 enzymatic activation. The interaction and activation depend exclusively on ITSM-Y248. Isothermal titration calorimetry (ITC), PD-1 dimerization in live cells, SHP-2 enzymatic activation assay with ITSM phosphopeptides, site-directed mutagenesis Communications biology High 32184441
2007 In zebrafish, Shp-2 is required for convergence and extension cell movements during gastrulation. Shp-2 knockdown-induced defects were rescued by active Fyn, active Yes (Src family kinases), and active RhoA, placing Src family kinases and RhoA downstream of Shp-2 in this process. Noonan syndrome Shp-2 mutants are activated (gain-of-function) while LEOPARD syndrome mutants lack catalytic activity; both cause convergence/extension defects. Morpholino knockdown in zebrafish, cell tracing experiments, epistatic rescue with constitutively active Fyn/Yes/RhoA, in situ hybridization, expression of patient-derived mutants PLoS genetics High 18159945
2011 The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy (HCM) by dysregulating mTOR signaling. Cardiomyocyte-specific overexpression of Q510E-Shp2 hyperactivated Akt/mTOR signaling, and rapamycin treatment rescued the HCM phenotype both prophylactically and therapeutically. Normal Shp-2 controls cardiomyocyte size by regulating Akt/mTOR. Cardiomyocyte-specific transgenic mouse model, Akt/mTOR phosphorylation (Western blot), rapamycin rescue, echocardiography, histology American journal of physiology. Heart and circulatory physiology High 22058153
2012 In Xenopus, SHP-2 regulates the cardiac actin cytoskeleton via ROCK. Noonan syndrome SHP-2 mutations cause cardiac cell cycle arrest in M-phase, failure of cardiomyocyte progenitors to incorporate into the developing heart, and defective actin fiber formation and polarity. ROCK inhibition rescued these cardiac defects, demonstrating that SHP-2(N308D) signals through ROCK to regulate the cardiac actin cytoskeleton. Xenopus cardiac development model, Noonan/JMML mutant SHP-2 expression, ROCK inhibitor rescue, F-actin staining, cardiac cell cycle analysis Development High 22278918
2007 In Xenopus, SHP-2 activity is required for maintenance and survival of proliferating cardiac progenitor cells. SHP-2 is phosphorylated on Y542/Y580 and binds to FRS-2, placing SHP-2 in the FGF pathway during early embryonic heart development. FGF signaling inhibition mimics SHP-2 inhibition effects, and constitutively active/Noonan-associated SHP-2 rescues FGF signaling inhibition. Xenopus cardiac progenitor assay, SHP-2 phosphorylation analysis (Y542/Y580), FRS-2 co-immunoprecipitation, FGF inhibitor phenocopy, constitutively active SHP-2 rescue Development High 17928416
2001 Shp-2 is required for lymphoid and hematopoietic cell development across all blood cell lineages. Shp-2-/- ES cells in RAG-2-deficient blastocyst complementation yielded no mature T or B cells, nor precursor lymphocytes. Shp-1 deficiency (me(v)/me(v)) partially rescued Shp-2-/- hematopoietic defects, demonstrating antagonistic roles for Shp-1 and Shp-2 in hematopoiesis via the same signaling pathway(s). RAG-2-deficient blastocyst complementation, double Shp-2-/-/mev/mev mutant analysis, yolk sac hematopoiesis quantification Blood High 11159516
2018 Large-scale phosphoproteomics identified Shp-2 as the master regulator of PDGF receptor (Pdgfr) pTyr signaling. Allosteric Shp-2 inhibition revealed global regulation of the Pdgf-dependent tyrosine phosphoproteome. Key Shp-2-dependent targets include Rasa1 and Cortactin (increased pTyr upon Shp-2 inhibition) and Gab1 and Erk1/2 (decreased pTyr). Shp-2 inhibition significantly impaired PDGF-stimulated cell migration. Quantitative phosphoproteomics (>40,000 phosphorylation sites), allosteric Shp-2 inhibitor (SHP099), cell migration assay Cell reports High 29514104
2011 Substrate specificity profiling by combinatorial peptide library screening established that SHP-2 shares similar but narrower substrate specificities with SHP-1: both strongly prefer acidic and aromatic hydrophobic amino acids flanking the pY residue, with preference for ≥2 acidic residues N-terminal and ≥1 acidic residue C-terminal to pY, and exclusion of basic residues. The in vitro specificity profile agreed with in vivo dephosphorylation patterns of known SHP-2 substrates. On-bead screening of combinatorial phosphotyrosyl peptide libraries, solution-phase kinetic analysis of individually synthesized pY peptides Biochemistry High 21291263
2012 SHP-2 regulates osteoclastogenesis by promoting preosteoclast fusion, required for formation of giant multinucleated osteoclasts. OC-specific Shp2 knockout mice are osteopetrotic. Shp-2 is required for RANKL-induced upregulation of Nfatc1 (master transcription factor for terminal OC differentiation). Shp-2 deletion had minimal effect on M-CSF-dependent OC precursor survival/proliferation. Osteoclast-specific conditional Shp2 knockout, microCT bone analysis, RANKL-induced Nfatc1 expression assay, cell fusion assay, pharmacological Shp2 inhibition FASEB journal High 25593124
2012 SHP-2 is required for leucine-induced S6K1 activation in skeletal myoblasts via mobilization of intracellular Ca2+ in an IP3-dependent manner. SHP-2 acts upstream of phospholipase C β4 to generate nutrient-induced Ca2+ release and S6K1 phosphorylation. SHP-2-deficient myoblasts have impaired leucine sensing, defective autophagy, and reduced myoblast size. SHP-2 knockout/overexpression in myoblasts, S6K1 phosphorylation assay, Ca2+ mobilization assay, IP3 measurement, PLC β4 epistasis, autophagy assay Molecular and cellular biology Medium 23129808
2019 Shp-2 is critical for ERK activation and metabolic engagement (glycolysis and respiration) downstream of IL-15 receptor in NK cells. Shp-2-deficient NK cells show dramatic defect in ERK activation and reduced metabolic burst upon IL-15/IL-2 stimulation, leading to impaired proliferation and survival. ERK and mTOR cascade inhibition phenocopied Shp-2 deficiency. NK cell-specific conditional Shp-2 KO, ERK phosphorylation assay, Seahorse metabolic flux analysis, pharmacological ERK/mTOR inhibitor epistasis Nature communications High 30926899
2018 Genetic deletion of Ptpn11 profoundly inhibits tumor development in mutant KRAS-driven pancreatic ductal adenocarcinoma (PDAC) and non-small-cell lung cancer mouse models. SHP-2 is necessary for resistance mechanisms upon MEK blockade. Dual SHP2/MEK inhibition achieves synergistic tumor growth control in KRAS-mutant PDAC and NSCLC. Genetic Ptpn11 deletion in KRAS-driven mouse tumor models, MEK inhibitor combination, patient-derived organoids and xenograft models Nature medicine High 29808009
2018 X-ray crystallography identified a second allosteric binding site on SHP2 at the interface of the N-terminal SH2 and PTP domains (distinct from the tunnel-like SHP099 site). SHP244 binds and stabilizes the inactive closed conformation of SHP2 at this site. Simultaneous occupation of both allosteric sites is possible, demonstrating cooperative dual allosteric inhibition and enhanced MAPK pathway suppression. X-ray crystallography of SHP2/inhibitor complexes, cooperative biochemical inhibition assays, DUSP6 mRNA assay in cancer cells, structure-based design ACS chemical biology High 29304282
2013 SHP-2 directly interacts with ICAM-1 and VE-cadherin in endothelial cells. SHP-2 downregulation enhanced neutrophil adhesion but inhibited transmigration. ICAM-1 activation leads to SHP-2-mediated Src activation and VE-cadherin switching from ICAM-1 association to actin association; SHP-2 downregulation prevented ICAM-1-VE-cadherin association and promoted VE-cadherin-actin association. siRNA knockdown of SHP-2, co-immunoprecipitation of ICAM-1/SHP-2/VE-cadherin, neutrophil adhesion/transmigration assay, in vivo LPS lung model FASEB journal Medium 28701303
2019 In sepsis, ROS-dependent inactivation of SHP-2 in endothelial cells drives vascular dysfunction. SHP-2 directly interacts with the IL-1R1 adaptor MyD88 via its tyrosine 257, resulting in reduced binding of p85/PI3K to MyD88. SHP-2 activity inversely correlates with adhesion molecule expression through p38 MAPK and NF-κB. Proximity ligation assay for SHP-2/MyD88 interaction, SHP-2 phosphatase activity assay, ROS inhibitor rescue, in vivo sepsis model, in vitro endothelial cell model, Y257 mutagenesis EBioMedicine Medium 30905847
2013 Intestinal epithelial cell-specific deletion of SHP-2 leads to severe colitis with hyperactivation of Stat3 and NF-κB, decreased claudin expression and enhanced intestinal permeability. Antibiotic treatment markedly impaired colitis development, indicating a microbiota-dependent mechanism. Intestinal epithelial cell-specific conditional KO (SHP-2(IEC-KO) mice), histology, cytokine analysis, intestinal permeability assay, Western blot for Stat3/NF-κB, antibiotic treatment Molecular and cellular biology High 23530062
2022 In myeloid cells, SHP-2 restrains GM-CSF-induced phosphorylation of transcription factors HOXA10 and IRF8, which regulate myeloid differentiation and monocytic-moDC lineage commitment. GM-CSF induces phosphorylation of PD-1 and recruitment of PD-1-SHP-2 to the GM-CSF receptor. Myeloid-specific deletion of SHP-2 or PD-1 diminishes tumor growth via enhanced myeloid differentiation. Myeloid-specific conditional SHP-2 or PD-1 KO mice, RNA-seq/GSEA, HOXA10/IRF8 phosphorylation assay, co-immunoprecipitation of PD-1-SHP-2 with GM-CSF receptor, tumor growth assay Nature immunology High 36581713
1999 BIT (brain immunoglobulin-like molecule with tyrosine-based activation motifs) associates with SHP-2 via its tyrosine-phosphorylated TAMs upon neurotrophin (NGF, BDNF, NT-3) stimulation, and this association potently stimulates SHP-2 phosphatase activity in neurons. Co-immunoprecipitation after neurotrophin treatment, in vitro SHP-2 phosphatase activation assay with pY-BIT Journal of neurochemistry Medium 10098842
2013 RSK (p90 ribosomal S6 kinase) phosphorylates Gab2 on conserved residues upon Ras/MAPK pathway activation, and this phosphorylation inhibits recruitment of SHP-2 to Gab2 in response to growth factors. An unphosphorylatable Gab2 mutant promotes invasion-like phenotype and increased cell motility, indicating that RSK-mediated Gab2 phosphorylation constitutes a negative-feedback loop restricting Gab2-dependent SHP-2 recruitment and epithelial cell motility. In vitro RSK kinase assay with Gab2, phosphosite mutagenesis, co-immunoprecipitation of Gab2-SHP-2 after growth factor stimulation, invasion/motility assay Molecular and cellular biology Medium 23401857
2014 Crystal structures of wild-type SHP2 and five NS/LS-associated PTPN11 mutants reveal local conformational changes caused by each mutation. NS mutations shift conformational equilibrium toward the active open state; LS mutations have distinct structural consequences consistent with loss of catalytic activity. Structural analysis provides mechanistic insight into the distinct catalytic properties of disease-associated mutants. X-ray crystallography of WT and mutant SHP2 proteins BMC structural biology High 24628801
2002 Gab1-SHP-2 interaction is required for EGF-induced Ras activation and epidermal proliferation. Gab1(Y627F) deficient in SHP-2 binding or dominant-negative SHP-2(C459S) reduced active Ras and downstream MAPK levels and initiated keratinocyte differentiation. Active Ras rescued the differentiation induced by Gab1(Y627F) and SHP-2(C459S), placing Gab1 and SHP-2 upstream of Ras in epidermal homeostasis. Gab1(Y627F) and SHP-2(C459S) overexpression in epidermal cells, Ras activity assay, Ras rescue epistasis, tissue reconstruction model, Gab1-/- murine epidermis analysis The Journal of cell biology High 12370245
2000 SHP-2 is required for Ras-dependent JNK activation by insulin and EGF. A catalytically inactive SHP-2(C/S) mutant markedly inhibited Ras activation in response to insulin without affecting insulin-induced tyrosine phosphorylation of substrates. SHP-2(C/S) did not inhibit JNK activation induced by constitutively active Ras(V12), placing SHP-2 at the level of or upstream of SOS in insulin-mediated JNK activation. Catalytically inactive SHP-2(C/S) overexpression, JNK/ERK activation assay, Ras-GTP loading assay, dominant-negative Ras/Rac epistasis, PI3K inhibitor The Journal of biological chemistry Medium 10671568
2004 SHP-2 catalytic activity suppresses caspase 3-mediated apoptosis by regulating IGF-1-dependent PI3K and Akt activation. Catalytically inactive SHP-2 inhibited IGF-1-induced PI3K and Akt activation; SHP-2(Ex3-/-) fibroblasts showed enhanced caspase 3 activation upon etoposide treatment, rescued by re-introduction of wild-type SHP-2 or a caspase 3 inhibitor. Catalytically inactive SHP-2 overexpression, SHP-2(Ex3-/-) fibroblasts, PI3K/Akt assay, caspase 3 activity assay, WT-SHP-2 rescue, RNAi knockdown Journal of cellular physiology Medium 15040005
2008 SHP-2 and Src are exclusively localized in brain (not muscle, heart, liver, or kidney) mitochondria. In brain mitochondria, ATP induces Src autophosphorylation at Tyr-416 (activation), and SHP-2 is present at this location; Src inhibition partially reversed ATP-induced increases in oxidative phosphorylation complexes I, III, and IV activity. Subcellular fractionation and immunodetection of PTP-1B, SHP-2, and Src in isolated mitochondria from multiple rat tissues, oxidative phosphorylation complex activity assays The Journal of biological chemistry Low 18583343
2002 In C2C12 myoblasts, FGF-2 stimulation induces SHP-2 complex formation with tyrosyl-phosphorylated FRS-2α. Both catalytic activity and (to a lesser extent) the Grb2-binding/tyrosyl-phosphorylation sites of SHP-2 are required for maximal FGF-2-induced Erk activation. A constitutively active SHP-2 mutant represses myogenesis via an Erk-independent pathway and induces hyper-tyrosyl phosphorylation of FRS-2α. Co-immunoprecipitation of SHP-2 with FRS-2α, Erk/Elk-1 activation assay, constitutively active and catalytically inactive SHP-2 overexpression, myogenesis assay Molecular and cellular biology Medium 11997521

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature genetics 1281 11704759
2001 SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science (New York, N.Y.) 828 11743164
1999 Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells. Developmental biology 431 10364425
1998 Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. The Journal of biological chemistry 343 9694867
2003 Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 332 14644997
2008 The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer metastasis reviews 326 18286234
2018 Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nature medicine 320 29808009
2009 SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels. Immunological reviews 304 19290938
1999 Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Molecular and cellular biology 288 10022928
2011 Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer cell 285 21575863
1999 Shp-2 tyrosine phosphatase: signaling one cell or many. Experimental cell research 245 10579910
2007 The role of Shp2 (PTPN11) in cancer. Current opinion in genetics & development 236 17227708
1994 Syp (SH-PTP2) is a positive mediator of growth factor-stimulated mitogenic signal transduction. The Journal of biological chemistry 231 8063747
2006 SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 207 17157040
2015 Functions of Shp2 in cancer. Journal of cellular and molecular medicine 204 26088100
2007 The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histology and histopathology 203 17647198
1993 Tyrosyl phosphorylation and growth factor receptor association of the human corkscrew homologue, SH-PTP2. The Journal of biological chemistry 193 8514779
2009 Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer science 186 19622105
2015 SHP2 sails from physiology to pathology. European journal of medical genetics 182 26341048
2004 Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation. Human mutation 159 14974085
2020 Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation. Communications biology 146 32184441
2005 A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cellular signalling 144 16084691
2000 The SHP-2 tyrosine phosphatase: signaling mechanisms and biological functions. Cell research 138 11191350
2001 The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors. Oncogene 135 11593409
2020 Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein. Journal of medicinal chemistry 132 32437146
2018 Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo. Cell reports 119 29617671
2000 The protein tyrosine phosphatase Shp-2 regulates RhoA activity. Current biology : CB 116 11114521
2002 Role of the SHP-2 tyrosine phosphatase in cytokine-induced signaling and cellular response. Biochimica et biophysica acta 109 12421673
1997 Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases. The Journal of biological chemistry 109 8995399
2000 Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction. Current opinion in immunology 103 10781410
2005 Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. Journal of human genetics 102 15834506
1998 Structural determinants of SHP-2 function and specificity in Xenopus mesoderm induction. Molecular and cellular biology 99 9418864
2001 Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood 97 11159516
2018 Dual Allosteric Inhibition of SHP2 Phosphatase. ACS chemical biology 95 29304282
2005 Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP. The EMBO journal 95 15933714
2003 Identification of Shp-2 as a Stat5A phosphatase. The Journal of biological chemistry 94 12615921
2004 SHP-2 and myeloid malignancies. Current opinion in hematology 93 14676626
2009 The tyrosine phosphatase Shp2 (PTPN11) directs Neuregulin-1/ErbB signaling throughout Schwann cell development. Proceedings of the National Academy of Sciences of the United States of America 92 19805360
1997 The protein-tyrosine phosphatase SHP-2 associates with tyrosine-phosphorylated adhesion molecule PECAM-1 (CD31). The Journal of biological chemistry 89 9388260
2011 Substrate specificity of protein tyrosine phosphatases 1B, RPTPα, SHP-1, and SHP-2. Biochemistry 87 21291263
2004 SHP-2 regulates the phosphatidylinositide 3'-kinase/Akt pathway and suppresses caspase 3-mediated apoptosis. Journal of cellular physiology 87 15040005
2004 SHP-2 positively regulates myogenesis by coupling to the Rho GTPase signaling pathway. Molecular and cellular biology 81 15169898
2007 Shp2 knockdown and Noonan/LEOPARD mutant Shp2-induced gastrulation defects. PLoS genetics 78 18159945
2011 SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. The Journal of clinical investigation 75 21393858
2002 Gab1 and SHP-2 promote Ras/MAPK regulation of epidermal growth and differentiation. The Journal of cell biology 75 12370245
2022 SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses. Nature immunology 74 36581713
1998 SHP-2, SH2-containing protein tyrosine phosphatase-2. The international journal of biochemistry & cell biology 74 9693956
2008 2-Thiazolylimino/heteroarylimino-5-arylidene-4-thiazolidinones as new agents with SHP-2 inhibitory action. Journal of medicinal chemistry 69 18702480
2006 Gain-of-function/Noonan syndrome SHP-2/Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling. Proceedings of the National Academy of Sciences of the United States of America 66 16461457
2008 Localization of PTP-1B, SHP-2, and Src exclusively in rat brain mitochondria and functional consequences. The Journal of biological chemistry 65 18583343
2014 Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC structural biology 63 24628801
2022 Targeting macrophagic SHP2 for ameliorating osteoarthritis via TLR signaling. Acta pharmaceutica Sinica. B 62 35865095
2011 The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling. American journal of physiology. Heart and circulatory physiology 61 22058153
2000 Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2. Journal of physiology, Paris 59 11088001
1997 Syk-independent tyrosine phosphorylation and association of the protein tyrosine phosphatases SHP-1 and SHP-2 with the high affinity IgE receptor. Journal of immunology (Baltimore, Md. : 1950) 59 9379041
1994 Dephosphorylation of insulin receptor substrate 1 by the tyrosine phosphatase PTP2C. The Journal of biological chemistry 57 7515062
2013 S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke. Proceedings of the National Academy of Sciences of the United States of America 55 23382182
2018 Large-Scale Phosphoproteomics Reveals Shp-2 Phosphatase-Dependent Regulators of Pdgf Receptor Signaling. Cell reports 53 29514104
2017 Role of SHP2 in hematopoiesis and leukemogenesis. Current opinion in hematology 53 28306669
2016 Tanshinone IIA induced cell death via miR30b-p53-PTPN11/SHP2 signaling pathway in human hepatocellular carcinoma cells. European journal of pharmacology 53 27894814
2012 Dual faces of SH2-containing protein-tyrosine phosphatase Shp2/PTPN11 in tumorigenesis. Frontiers of medicine 47 22869052
2019 SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling. Frontiers in immunology 46 31708921
2002 Role of SHP-2 in fibroblast growth factor receptor-mediated suppression of myogenesis in C2C12 myoblasts. Molecular and cellular biology 45 11997521
2008 SHP-2 is a novel target of Abl kinases during cell proliferation. Journal of cell science 42 18827006
2018 The Landscape of Protein Tyrosine Phosphatase (Shp2) and Cancer. Current pharmaceutical design 41 30398108
2016 Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies. Proceedings of the National Academy of Sciences of the United States of America 40 26755576
2009 The protein tyrosine phosphatase SHP-2 is required for EGFRvIII oncogenic transformation in human glioblastoma cells. Experimental cell research 39 19427850
2019 Shp-2 is critical for ERK and metabolic engagement downstream of IL-15 receptor in NK cells. Nature communications 38 30926899
2013 Epithelial tyrosine phosphatase SHP-2 protects against intestinal inflammation in mice. Molecular and cellular biology 37 23530062
2011 PTPN11-associated mutations in the heart: has LEOPARD changed Its RASpots? Trends in cardiovascular medicine 37 22681964
2009 SHP-2 expression negatively regulates NK cell function. Journal of immunology (Baltimore, Md. : 1950) 37 19915046
1999 Tyrosine phosphorylation and association of BIT with SHP-2 induced by neurotrophins. Journal of neurochemistry 37 10098842
2013 Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies. Molecular cancer therapeutics 36 23825065
2012 Shp-2 regulates the TrkB receptor activity in the retinal ganglion cells under glaucomatous stress. Biochimica et biophysica acta 36 22878065
2000 Requirement for protein-tyrosine phosphatase SHP-2 in insulin-induced activation of c-Jun NH(2)-terminal kinase. The Journal of biological chemistry 35 10671568
2005 Tyrosine phosphatase SHP-2 is a mediator of activity-dependent neuronal excitotoxicity. The EMBO journal 33 15650750
2023 Macrophage-derived SHP-2 inhibits the metastasis of colorectal cancer via Tie2-PI3K signals. Oncology research 32 37304233
2013 Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis. Scientific reports 32 24088816
2013 Expression and clinical significance of tyrosine phosphatase SHP-2 in colon cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 32 24439672
2006 SHP-2 phosphatase is required for hematopoietic cell transformation by Bcr-Abl. Blood 32 17003374
2007 SHP-2 is required for the maintenance of cardiac progenitors. Development (Cambridge, England) 30 17928416
2015 SHP2 regulates osteoclastogenesis by promoting preosteoclast fusion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 25593124
2010 Integrin beta4 attenuates SHP-2 and MAPK signaling and reduces human lung endothelial inflammatory responses. Journal of cellular biochemistry 29 20512931
2016 SHP-2 phosphatase controls aryl hydrocarbon receptor-mediated ER stress response in mast cells. Archives of toxicology 28 27709270
2013 Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility. Molecular and cellular biology 28 23401857
2022 SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2. Oncogene 26 35034964
2019 Pathogenic variants of DYNC2H1, KIAA0556, and PTPN11 associated with hypothalamic hamartoma. Neurology 26 31197031
2003 Gab1, SHP-2 and other novel regulators of Ras: targets for anticancer drug discovery? Current cancer drug targets 26 12769687
2022 Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery. Medicinal research reviews 25 35575058
2019 Inactivation of the tyrosine phosphatase SHP-2 drives vascular dysfunction in Sepsis. EBioMedicine 25 30905847
2012 SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton. Development (Cambridge, England) 25 22278918
2012 Novel role for SHP-2 in nutrient-responsive control of S6 kinase 1 signaling. Molecular and cellular biology 25 23129808
2009 Polymorphisms of PTPN11 coding SHP-2 as biomarkers for ulcerative colitis susceptibility in the Japanese population. Journal of clinical immunology 25 19160029
2019 PTPN11 (SHP2) Is Indispensable for Growth Factors and Cytokine Signal Transduction During Bovine Oocyte Maturation and Blastocyst Development. Cells 24 31635340
2015 New and Unexpected Biological Functions for the Src-Homology 2 Domain-Containing Phosphatase SHP-2 in the Gastrointestinal Tract. Cellular and molecular gastroenterology and hepatology 24 28174704
2014 Distinct and overlapping functions of ptpn11 genes in Zebrafish development. PloS one 23 24736444
2001 SHP-2 complex formation with the SHP-2 substrate-1 during C2C12 myogenesis. Journal of cell science 23 11493654
1999 Tyrosine phosphatase SHP-2 dephosphorylates the platelet-derived growth factor receptor but enhances its downstream signalling. The Biochemical journal 23 9931295
2022 Targeting SHP2 phosphatase in hematological malignancies. Expert opinion on therapeutic targets 22 35503226
2017 Endothelial cell SHP-2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM-1-VE-cadherin interaction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 28701303

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