PTPN6 Human
Description
Introduction to PTPN6 Human
PTPN6 (Protein Tyrosine Phosphatase Non-Receptor Type 6), also known as SHP-1, is a non-receptor tyrosine phosphatase encoded by the PTPN6 gene on chromosome 12p13.31 . This enzyme plays a critical role in regulating cellular signaling pathways, particularly in hematopoietic cells, by dephosphorylating tyrosine residues on target proteins . The human recombinant form, PTPN6 Human, is a 34.3 kDa protein produced in Escherichia coli, comprising 300 amino acids with catalytic activity (>5,000 U/mg) .
Molecular Architecture
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Domains: Contains two Src homology 2 (SH2) domains at the N-terminus and a catalytic phosphatase domain at the C-terminus .
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Isoforms: Two promoter regions (P1 and P2) drive expression of distinct isoforms—PTPN6 1A (non-hematopoietic cells) and PTPN6 1B (hematopoietic cells) .
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Amino Acid Sequence: The catalytic domain (residues 243–541) includes the active site critical for phosphatase activity .
Biological Role
PTPN6 acts as a negative regulator of signaling pathways, including:
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STAT3 Signaling: Dephosphorylates STAT3 to inhibit oncogenic signaling .
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Immune Regulation: Modulates T-cell activation, lymphocyte differentiation, and cytokine responses .
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Hematopoiesis: Essential for maintaining hematopoietic cell homeostasis .
Table 1: Key Interacting Proteins of PTPN6
| Protein | Interaction Role | Source |
|---|---|---|
| JAK2/3 | Regulates JAK-STAT pathway activity | |
| CD22/CD31 | Mediates B-cell receptor signaling | |
| EGFR | Inhibits growth factor signaling | |
| SYK | Modulates immune cell activation |
Mutations in Disease
Loss-of-function mutations in PTPN6 (e.g., N225K and A550V) are linked to:
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Diffuse Large B-Cell Lymphoma (DLBCL): Mutations reduce phosphatase activity by 50–70%, leading to sustained STAT3 phosphorylation and oncogene activation (e.g., MCL1, SURVIVIN) .
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Autoimmune Disorders: Murine models with Ptpn6 mutations exhibit lupus-like syndromes and myeloid hyperplasia .
Table 2: Impact of PTPN6 Mutations in DLBCL3
| Mutation | STAT3 Phosphorylation | JAK3 Binding | Cell Proliferation |
|---|---|---|---|
| Wild-Type | Suppressed | Moderate | Inhibited |
| N225K | Sustained | Enhanced | Promoted |
| A550V | Sustained | Enhanced | Promoted |
Pan-Cancer Analysis
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Prognostic Marker: High PTPN6 expression correlates with poor survival in LGG, KIRC, and TGCT but improved outcomes in BRCA and LUAD .
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Immune Infiltration: Elevated PTPN6 levels associate with increased B-cell, CD8+ T-cell, and dendritic cell infiltration in tumors like KIRC and LGG .
Biochemical Properties
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Activity: Hydrolyzes p-nitrophenylphosphatase at >5,000 U/mg .
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Stability: Stable at -20°C with 0.1% HSA/BSA carrier protein .
Experimental Use
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Drug Discovery: Screens for inhibitors targeting STAT3-driven cancers .
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Mechanistic Studies: Elucidates phosphatase-substrate dynamics in immune signaling .
STAT3 Deregulation in Lymphoma
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Mutant PTPN6 (N225K/A550V) fails to suppress STAT3 phosphorylation, enabling resistance to JAK3 inhibitors (e.g., WHIP-154) and promoting tumor survival .
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In vitro studies show mutant PTPN6 increases MCL1 and SURVIVIN expression by 2–3 fold compared to wild-type .
Epigenetic Regulation in Cancer
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Hypomethylation of PTPN6 correlates with overexpression in 8/12 tumor types, including breast and liver cancers .
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Phosphorylation sites (e.g., Tyr-536) are altered in 6 cancers, affecting substrate binding .
Table 3: Pan-Cancer PTPN6 Expression and Survival4
| Cancer Type | Expression vs. Normal | Prognostic Impact |
|---|---|---|
| LGG | Upregulated | Poor OS |
| KIRC | Upregulated | Poor OS |
| BRCA | Upregulated | Improved OS |
| LUAD | Downregulated | Improved OS |
Product Specs
Product Science Overview
The PTPN6 protein contains two tandem Src homology 2 (SH2) domains at its N-terminal, which act as protein phospho-tyrosine binding domains. These domains mediate the interaction of PTPN6 with its substrates . The primary function of PTPN6 is to dephosphorylate a wide spectrum of phospho-proteins involved in hematopoietic cell signaling .
PTPN6 is primarily expressed in hematopoietic cells, where it functions as an important regulator of multiple signaling pathways . The expression of SHP-1 is regulated by two promoters: P-1, which is active in epithelial cells, and P-2, which is active in hematopoietic cells . Interestingly, the expression levels of SHP-1 vary between cell types and can change in response to cancer, with increased levels in epithelial cells and decreased levels in hematopoietic cells .
Recombinant human PTPN6 is used extensively in research to study its role in cell signaling and its potential as a therapeutic target. The availability of human recombinant PTPN6 allows for detailed biochemical studies and the development of inhibitors that could modulate its activity in disease contexts .
