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FLASH GENE

Symbol

PTPN6

contributors: mct/npt/pgu - updated : 10-04-2013

HGNC name	protein tyrosine phosphatase, non-receptor type 6
HGNC id	9658

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive esophagus       moderately   intestine small intestine     moderately Endocrine thyroid       moderately Lymphoid/Immune spleen       predominantly   thymus       highly   tonsils       highly Respiratory lung       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     highly Homo sapiens Adult Connective bone       Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic mature hematopoietic Homo sapiens Adult Lymphoid/Immune T cell

cell lineage	hematopoietic cell lineage
cell lines
fluid/secretion	blood, lymph

at STAGE

PROTEIN

PHYSICAL PROPERTIES		basic
STRUCTURE

motifs/domains	two tandemly repeated SH2 domains at N terminus, that is implicated as providing suppression of hematopoietic malignancies
	three proline-rich, potential SH3-binding motifs, SH3 domain- containing CRKL adaptor protein associating with PTPN6
	a tyrosine-phosphatase catalytic domain in C terminal region
	C terminal nuclear localization signal (short cluster of basic AA : KRK), and six-AAs, lipid raft-targeting motif, necessary and sufficient for lipid raft localization and for the function as a negative regulator of TCR signaling

conjugated

PhosphoP

mono polymer

monomer

HOMOLOGY

interspecies	homolog to rattus Ptpn6 (94.1pc)
	homolog to murine Ptpn6 (94.5pc)

intraspecies

homolog to PTPN11

Homologene

FAMILY	protein-tyrosine phosphatase family
	non-receptor class 2 subfamily

CATEGORY

enzyme , signaling

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	lipid raft localization
	elevation of NaCl significantly decreases the fraction of PTPN6 that is in the nucleus and lowering NaCl does the opposite

basic FUNCTION	negative regulator of cell signaling in T cells
	limiting antiapoptotic signal
	playing a key role in hematopoiesis
	may directly link growth factor receptors and other signaling proteins through protein-tyrosine phosphorylation via its PTPase activity
	downregulating IL-3 inducing tyrosine phosphorylation and mitogenesis
	involved in the regulation of glucose homeostasis through modulation of insulin signaling in liver and muscle as well as hepatic insulin clearance
	playing a role with PTPRK in the regulation, maintenance, and restitution of cell adhesions in a complex epithelial organ such as the pancreas
	key negative regulator of TCR-mediated signaling
	negatively regulated Toll-like receptor-mediated production of proinflammatory cytokines by inhibiting activation of the transcription factor NF-kappaB and mitogen-activated protein kinase
	contributes to immune homeostasis by balancing the production of proinflammatory cytokines and type I interferons in the innate immune response
	involved in the inhibition of CD2 signaling (represents a novel mechanism for direct T cell suppression by IL10)
	playing an important role in airway mucin production through regulating oxidative stress
	regulates cell growth, inflammation, and injury largely through negative signaling, as by inhibition of STATs, NF-KB, ERK, and the PI3 kinase-Akt pathway
	regulates cell proliferation, whether it is by controlling mitogenic pathways activated by receptors with tyrosine kinase activity, or by regulating components of the cell-cycle machinery
	intrinsic global regulator of dendritic cell function, controlling many facets of T cell-mediated immune responses
	novel role for PTPN6 in the regulation of AKT1 activity through the modulation of the ghrelin/GHSR1a system signaling
	regulates muscle insulin action in a cell-autonomous manner, further suggesting that the PTPase negatively modulates insulin action through down-regulation of both insulin signaling to AKT1 and SLC2A4 translocation, as well as SLC2A4 expression
	negative regulator of proinflammatory signaling and autoimmune disease
	key regulator of dendritic cell functions that protects against autoimmunity
	role in the regulation of signaling or membrane fusion events involved in phagolysosome biogenesis
	possible involvement of the PTPN6 phosphatase in regulating other NK functions in mature NK cells

CELLULAR PROCESS	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

development

text	hematopoietic cell development

PATHWAY

metabolism

signaling

signal transduction

a component	forms a complex with receptor activator of NF-kB (TNFRSF11A), LYN and the adapter protein, Grb2-associated binder 2 (GAB2)
	PLCB3 form the multimolecular SPS complex together with PTPN6 and STAT5

INTERACTION

DNA

RNA

small molecule

protein	CSF2RB
	activated KIT
	LAIR1
	death receptor of TNF (block antiapoptotic signaling in neutrophils)
	TFG is a novel protein able to modulate PTPN6 activity
	directly binding to and inhibiting activation of the kinase IRAK1, increasing the production of type I interferon mediated by Toll-like receptors and the helicase DDX58
	STAT3
	DNMT1
	HDAC1
	physically interact with PTPN6, and age-specific interactions between SIGLEC9 and PTPN6 may influence the altered inflammatory responsiveness and longevity of neonatal polymorphonuclear neutrophils
	interacting with NFAT5 (Overexpression of PTPN6 greatly decreases high NaCl-induced nuclear localization of native NFAT5)
	LYN/PLCB3-mediated regulatory mechanism of PTPN6 and STAT5B activities
	in liver, transcriptional activation of PTPN6 gene by PKNOX1 attenuates insulin signal transduction and reduces glucose storage
	negatively regulates the nuclear transcriptional function of CTNNB1
	SIGLEC12 binds to the tyrosine phosphatases PTPN6 and PTPN11 in a phosphorylation-dependent manner
	inducibly interacts with the SH2 domain of SH3BP2 after the aggregation of FCER1A
	CRKL adaptor protein associating with PTPN6
	is an essential negative regulator of IL4 signaling in T lymphocytes
	inhibitory action of RAP1B on PI3K signaling may be mediated by activation of phosphatase PTPN6
	ERK-1/2 inhibition or MAPK14 overexpression inhibited CD40-induced PTPN6 activation

cell & other

REGULATION

Other

regulated by USF1 and USF2

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   overexpressed in severe congenital neutropenia tumoral     --low   by aberrant methylation in leukemias/lymphomas constitutional     --low   in multiple sclerosis (MS)patients with, heightened STAT6 phosphorylation, and an enhanced state of activation relevant to the mechanisms of inflammatory demyelination , and in over a third of MS subjects, abnormally high promoter methylation constitutional       loss of function inactivation contributes to high NaCl-induced increase in NFAT5 transactivating activity constitutional     --other   defect in transcriptional regulation of the hematopoietic PTPN6 appears to be involved in the pathogenesis of certain subsets of the heterogeneous group of neutrophilic dermatoses

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	of MS, low expression in serum due, in over a third of MS subjects, to abnormally high promoter methylation
Therapy target
	System Type Disorder Pubmed cancer     therapeutic target for cancer treatment

ANIMAL & CELL MODELS