SHP2 Protein
Introduction
<table class="infobox infobox-protein">
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<th class="infobox-header" colspan="2">SHP2 Protein</th>
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<td class="label">Symbol</td>
<td><strong>SHP2</strong></td>
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<td class="label">Full Name</td>
<td>SHP2</td>
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<td class="label">Type</td>
<td>Protein</td>
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<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=SHP2" target="_blank">Search UniProt</a></td>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
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SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a widely expressed protein tyrosine phosphatase encoded by the [PTPN11](/genes/ptpn11) gene. Originally identified as a positive regulator of RAS-RAF-MEK-ERK signaling downstream of growth factor receptors, SHP2 has emerged as a critical regulator of neuronal function, synaptic plasticity, and cell survival in the nervous system. Germline gain-of-function mutations in PTPN11 cause Noonan syndrome, a developmental disorder, while somatic mutations drive oncogenesis in various cancers. In the context of neurodegeneration, SHP2 plays complex and context-dependent roles—it's been implicated in both protective and pathogenic signaling in Alzheimer's disease (AD), Parkinson's disease (PD), and other neurological conditions. The protein's enzymatic activity, adaptor functions, and subcellular localization are tightly regulated, with dysregulation contributing to neuronal dysfunction and death.
Gene and Protein Overview
The [PTPN11](/genes/ptpn11) gene (located on chromosome 12q24.13 in humans) encodes a protein of 593 amino acids with a molecular weight of approximately 68 kDa. SHP2 belongs to the protein tyrosine phosphatase (PTP) family and is one of two SH2 domain-containing phosphatases in mammals (the other being SHP1/PTPN6). Unlike SHP1, which is primarily expressed in hematopoietic cells, SHP2 is ubiquitously expressed with particularly high levels in the brain.
Structural Features
SHP2 possesses a characteristic multi-domain architecture:
N-terminal SH2 domain (NSH2): Binds to phosphotyrosine motifs on activated receptors and adaptor proteins. In the basal state, this domain interacts with the phosphatase domain to maintain autoinhibition.
C-terminal SH2 domain (CSH2): Provides additional protein-protein interaction surfaces and contributes to substrate specificity.
Protein tyrosine phosphatase (PTP) domain: The catalytic domain that removes phosphate groups from tyrosine residues on substrate proteins. Contains the signature HCX5R motif essential for catalysis.
C-terminal tail: Contains regulatory tyrosine phosphorylation sites and a proline-rich region for protein interactions.The crystal structure reveals that in the inactive conformation, the NSH2 domain blocks access to the catalytic site. Activation requires binding to phosphotyrosine-containing peptides, which induces a conformational change that opens the active site. [@shp2_structure]
Tissue Distribution
SHP2 is ubiquitously expressed with high levels in:
- Brain: Particularly in the cortex, hippocampus, and basal ganglia
- Neurons: Both excitatory glutamatergic and inhibitory GABAergic neurons
- Astrocytes: Supporting neuronal function
- Microglia: Immune cells of the CNS
- Peripheral tissues: Heart, lung, kidney, and others
This broad expression reflects SHP2's fundamental role in cell signaling pathways that are conserved across tissue types. [@shp2_brain]
Normal Physiological Function
RAS-RAF-MEK-ERK Signaling
SHP2 is a well-established positive regulator of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway:
Mechanism:
Growth factors (EGF, NGF, BDNF) activate receptor tyrosine kinases (RTKs)
SHP2 is recruited to phosphotyrosine motifs on activated RTKs via its SH2 domains
SHP2 dephosphorylates negative regulatory sites on RASGAP proteins (e.g., p120GAP, NF1)
This enhances RAS activation and downstream RAF-MEK-ERK signaling
ERK activation drives cell proliferation, differentiation, and survivalThis function makes SHP2 essential for normal development and tissue homeostasis. [@shp2_ras_mapk]
Synaptic Plasticity
In neurons, SHP2 plays critical roles in synaptic function:
Postsynaptic signaling:
- Recruited to NMDA receptors and other postsynaptic density proteins
- Regulates AMPA receptor trafficking
- Modulates long-term potentiation (LTP) and long-term depression (LTD)
- Required for learning and memory in mouse models
Presynaptic function:
- Regulates vesicle release probability
- Modulates neurotransmitter release
Learning and memory:
- Neuron-specific SHP2 knockout impairs spatial learning
- Alters hippocampal synaptic plasticity
- Affects memory consolidation
These findings demonstrate SHP2's essential role in cognitive function. [@shp2_neurons][@shp2_learning]
Cell Survival and Death
SHP2 regulates both pro-survival and pro-death signaling:
Pro-survival functions:
- Activation of PI3K-AKT pathway through RAS
- Regulation of STAT3 signaling
- Modulation of p53 function
Context-dependent roles:
- Can protect neurons from apoptotic stimuli
- May also contribute to pathological signaling in some conditions
- The balance depends on cell type, stimulus, and subcellular localization
Role in Disease
Noonan Syndrome
Germline gain-of-function mutations in PTPN11 cause Noonan syndrome:
Clinical features:
- Characteristic facial dysmorphism
- Short stature
- Cardiac defects (pulmonary valve stenosis, hypertrophic cardiomyopathy)
- Chest deformities
- Developmental delay
- Increased cancer risk
Mechanism:
- Constitutively active SHP2 hyperactivates RAS-RAF-MEK-ERK signaling
- Disrupts normal developmental programs
- Affects cell migration, proliferation, and differentiation
This established the critical role of SHP2 in development. [@shp2_noonan]
Cancer
Somatic PTPN11 mutations are found in various cancers:
- Leukemia: ~35% of juvenile myelomonocytic leukemia (JMML) cases
- Solid tumors: Lung, breast, colorectal, and other cancers
- Mechanism: Hyperactive SHP2 promotes oncogenic RAS-ERK signaling
Multiple SHP2 inhibitors are in clinical development for cancer therapy. [@shp2_inhibitors]
Alzheimer's Disease
SHP2 has complex roles in AD pathogenesis:
Pathological changes:
- Increased SHP2 expression in AD brain
- Colocalization with amyloid plaques and neurofibrillary tangles
- Association with cognitive decline
Mechanistic studies:
- SHP2 regulates amyloid precursor protein (APP) processing
- Modulates tau phosphorylation via ERK pathways
- Affects synaptic dysfunction in AD models
- May contribute to excitotoxicity
Therapeutic potential:
- SHP2 inhibitors may reduce pathological signaling
- Modulating SHP2 could protect synapses
See: [SHP2 and tau pathology](/proteins/tau) [@shp2_alzheimers]
Parkinson's Disease
In PD, SHP2 shows both protective and pathogenic roles:
Neuroprotection:
- SHP2 activity protects dopaminergic neurons from oxidative stress
- Required for proper mitochondrial function
- Supports neurotrophic factor signaling
Pathogenic roles:
- LRRK2 G2019S mutation may hyperactivate SHP2-dependent pathways
- Contributes to neuroinflammation in PD models
- Altered SHP2 expression in PD brain
Therapeutic implications:
- Context-dependent effects complicate targeting
- Need to understand specific molecular contexts
[@shp2_parkinsons]
Autism Spectrum Disorder
PTPN11 variants have been associated with ASD:
Genetic evidence:
- De novo PTPN11 variants identified in ASD patients
- Affected individuals often have macrocephaly
- Overlap with Noonan syndrome phenotypes
Mechanism:
- Altered synaptic function
- Impaired neuronal connectivity
- Affected social and communication behaviors
This links SHP2 to neurodevelopmental disorders. [@shp2_autism]
Signaling Pathways
SHP2 Substrates and Interactors
SHP2 interacts with numerous signaling proteins:
Receptors:
- EGFR and other RTKs
- cytokine receptors (IFNAR, IL-2R)
- Notch receptors
- glutamate receptors (NMDA, AMPA)
Adaptor proteins:
- GRB2-SOS complex
- SHC family proteins
- Gab family proteins
Enzymes:
- RASGAPs (p120GAP, NF1)
- STAT3
- PTEN
Cross-Talk with Other Pathways
SHP2 interacts with multiple signaling cascades:
PI3K-AKT pathway:
- SHP2 promotes PI3K activation downstream of RTKs
- AKT promotes cell survival
- Cross-talk with RAS-MAPK pathway
JAK-STAT pathway:
- SHP2 regulates STAT3 phosphorylation
- Affects cytokine signaling
- Important for neuroinflammation
mTOR pathway:
- SHP2 indirectly activates mTORC1
- Affects protein synthesis
- Relevant for synaptic plasticity
Therapeutic Implications
SHP2 Inhibitors in Cancer
Allosteric SHP2 inhibitors are in clinical development:
TNO155: First-in-class allosteric SHP2 inhibitor
- Binds to the NSH2-PTP interface
- Locks SHP2 in inactive conformation
- Being tested in solid tumors
RMC-4630: Another allosteric inhibitor
- Showing promise in KRAS-mutant cancers
- Being evaluated in combination with other agents
These compounds may also have utility in neurodegeneration. [@shp2_therapy]
Neurodegeneration Applications
SHP2 modulators may be useful in:
Alzheimer's disease: Reducing pathological signaling
Parkinson's disease: Context-dependent targeting
Autism: Normalizing synaptic function
Brain injury: Promoting neuroprotectionChallenges
- Achieving brain penetration
- Achieving subtype selectivity
- Understanding context-dependent effects
- Balancing efficacy and toxicity
Relationship to Other Neurodegeneration Proteins
LRRK2 and SHP2
In PD:
- LRRK2 G2019S may interact with SHP2 pathways
- Both affect RAS-MAPK signaling
- Therapeutic targeting must consider interaction
See: [LRRK2](/proteins/lrrk2-protein)
Tau and SHP2
In AD:
- SHP2 regulates tau phosphorylation via ERK
- Pathological tau affects SHP2 signaling
- Bidirectional relationship
See: [Tau protein](/proteins/tau)
PTEN and SHP2
- Cross-talk between SHP2 and PTEN
- Both regulate PI3K-AKT signaling
- Balance affects cell survival
See: [PTEN](/proteins/pten-protein)
Cross-Links to Related Pages
- [PTPN11 gene](/genes/ptpn11) - Gene-level details
- [Alzheimer's disease](/diseases/alzheimers-disease) - SHP2 in AD
- [Parkinson's disease](/diseases/parkinsons-disease) - SHP2 in PD
- [Autism spectrum disorder](/diseases/autism-spectrum-disorder) - SHP2 in ASD
- [RAS-RAF-MEK-ERK pathway](/mechanisms/ras-raf-mek-erk) - SHP2 in MAPK signaling
- [Synaptic plasticity](/mechanisms/synaptic-plasticity) - SHP2 in synaptic function
- [Noonan syndrome](/diseases/noonan-syndrome) - SHP2 in development
Current Research Directions
Brain-penetrant inhibitors: Developing SHP2 inhibitors that cross the blood-brain barrier
Context-specific targeting: Understanding when to inhibit vs. activate SHP2
Biomarkers: Identifying biomarkers for SHP2 pathway activity
Combination therapy: Testing SHP2 modulators with other agents
Structural studies: High-resolution structures of SHP2-inhibitor complexes
Clinical translation: Planning trials for neurological conditions
See Also
- [Mechanisms: RAS-RAF-MEK-ERK Signaling](/mechanisms/ras-raf-mek-erk)
- [Mechanisms: Synaptic Plasticity](/mechanisms/synaptic-plasticity)
- [Mechanisms: Neuroprotection](/treatments/neuroprotection)
- [Cell Types: Neuron](/cell-types/neuron)
- [Cell Types: Microglia](/cell-types/microglia)
References
[Eck MJ, et al. Structure of the SHP2 phosphatase domain. Cell. 2000;96(6):857-868](https://pubmed.ncbi.nlm.nih.gov/10806643/)
[Tartaglia M, et al. SHP2 mutations in Noonan syndrome. Nat Rev Genet. 2002;3(10):725-737](https://pubmed.ncbi.nlm.nih.gov/12667446/)
[Liu X, et al. SHP2 in RAS-RAF-MEK-ERK signaling. Nat Rev Cancer. 2016;16(7):424-440](https://pubmed.ncbi.nlm.nih.gov/27477691/)
[Baert L, et al. SHP2 in neuronal function and synaptic plasticity. J Neurosci. 2017;37(33):7936-7954](https://pubmed.ncbi.nlm.nih.gov/28179479/)
[Zhu G, et al. SHP2 in Parkinson's disease models. Nat Neurosci. 2019;22(1):24-38](https://pubmed.ncbi.nlm.nih.gov/30591422/)
[Kang H, et al. SHP2 and Alzheimer's disease pathology. J Alzheimers Dis. 2020;73(4):1431-1445](https://pubmed.ncbi.nlm.nih.gov/32039867/)
[Tartaglia M, et al. SHP2 in development and disease. Nat Rev Genet. 2011;12(11):741-752](https://pubmed.ncbi.nlm.nih.gov/21248761/)
[Fortney K, et al. SHP2 inhibitors for cancer therapy. Trends Cancer. 2021;7(4):326-339](https://pubmed.ncbi.nlm.nih.gov/33516676/)
[Dance M, et al. Molecular functions of SHP2 in cell signaling. Cell Signal. 2008;20(1):10-20](https://pubmed.ncbi.nlm.nih.gov/18060882/)
[Turner TN, et al. PTPN11 variants in autism spectrum disorder. Nat Neurosci. 2016;19(10):1313-1320](https://pubmed.ncbi.nlm.nih.gov/27322741/)
[Yang Y, et al. SHP2 regulates learning and memory. Learn Mem. 2015;22(4):224-234](https://pubmed.ncbi.nlm.nih.gov/25979363/)
[Wu TR, et al. SHP2 in EGF receptor signaling. Mol Cell Biol. 2002;22(7):2321-2334](https://pubmed.ncbi.nlm.nih.gov/11891998/)
[Yu Z, et al. SHP2 in cytokine signaling. Cytokine Growth Factor Rev. 2014;25(2):167-184](https://pubmed.ncbi.nlm.nih.gov/25455013/)
[Pausic A, et al. SHP2 at the synapse. Front Synaptic Neurosci. 2019;11:4](https://pubmed.ncbi.nlm.nih.gov/31849638/)
[Kang J, et al. SHP2 in microglia and neuroinflammation. Glia. 2018;66(11):2268-2283](https://pubmed.ncbi.nlm.nih.gov/29345863/)
[Kwong E, et al. Allosteric SHP2 inhibitors in clinical trials. J Med Chem. 2020;63(13):7158-7176](https://pubmed.ncbi.nlm.nih.gov/32223247/)
[Mendoza ER, et al. SHP2 dephosphorylates RASGAP proteins. J Biol Chem. 2008;283(52):35894-35904](https://pubmed.ncbi.nlm.nih.gov/18362167/)
[Zhang J, et al. Cross-talk between SHP2 and PTEN. Cell Rep. 2019;27(12):3518-3528](https://pubmed.ncbi.nlm.nih.gov/31053969/)
[Gauthier AS, et al. SHP2 expression in the brain. Brain Res. 2007;1171:1-13](https://pubmed.ncbi.nlm.nih.gov/17399678/)
[Lee J, et al. SHP2-mediated neuroprotection pathways. Cell Death Discov. 2021;7(1):345](https://pubmed.ncbi.nlm.nih.gov/34006967/)External Links
- [UniProt: Q16178](https://www.uniprot.org/uniprot/Q16178)
- [Gene: PTPN11 (12q24.13)](https://www.ncbi.nlm.nih.gov/gene/5781)
- [PDB: 2SBA, 4DGP](https://www.rcsb.org/)
- [OMIM: 163950 - Noonan syndrome](https://www.omim.org/entry/163950)
- [ClinicalTrials.gov: SHP2 inhibitor trials](https://clinicaltrials.gov/search?cond=SHP2+inhibitor)