AiPD: Autoinhibited Protein Database

P35235

Gene name	Ptpn11
Protein name	Tyrosine-protein phosphatase non-receptor type 11
Names	Protein-tyrosine phosphatase SYP, SH-PTP2, SHP-2, Shp2
Species	Mus musculus (Mouse)
KEGG Pathway	mmu:19247
EC number	3.1.3.48: Phosphoric monoester hydrolases
Protein Class

Descriptions

SHPTP2 is a widely-expressed Src homology 2 (SH2) domain-containing protein tyrosine phosphatase (PTP) that is important for normal cell development. It plays a critical role in a variety of signal transduction pathways, including growth factor-mediated cell proliferation Regulation of SHPTP2 activity is, in part, achieved by an intramolecular interaction between the PTP domain of the protein, which contains the catalytic site, and the N-SH2 domain leading to a 쐁losed protein conformation and autoinhibition. Accordingly, 쐎pening of the N-SH2 and PTP domains is required for the protein to become active. The binding of phosphopeptides to the N-SH2 domain is known to induce the opening event.

Autoinhibitory domains (AIDs)

1-103 (N-SH2 domain) SS

Target domain	246-523 (PTP domain)
Relief mechanism	Ligand binding
Assay

AID

1-103 (N-SH2 domain)

Target domain

246-523 (PTP domain)

Relief mechanism

Ligand binding (Binding of phosphopeptides)

Assay

Accessory elements

No accessory elements

References

Tartaglia M et al. (2010) "Noonan syndrome: clinical aspects and molecular pathogenesis", Molecular syndromology, 1, 2-26

Darian E et al. (2011) "Structural mechanism associated with domain opening in gain-of-function mutations in SHP2 phosphatase", Proteins, 79, 1573-88

Garcia Fortanet J et al. (2016) "Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor", Journal of medicinal chemistry, 59, 7773-82

LaRochelle JR et al. (2018) "Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition", Nature communications, 9, 4508

Hou Y et al. (2023) "How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2", RSC advances, 13, 4263-4274

Wu X et al. (2019) "Small Molecule Inhibitor that Stabilizes the Autoinhibited Conformation of the Oncogenic Tyrosine Phosphatase SHP2", Journal of medicinal chemistry, 62, 1125-1137

Shen D et al. (2020) "Therapeutic potential of targeting SHP2 in human developmental disorders and cancers", European journal of medicinal chemistry, 190, 112117

Pei D et al. (1994) "Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology 2 domains", Biochemistry, 33, 15483-93

Wang W et al. (2011) "Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation", Journal of cellular biochemistry, 112, 2062-71

Autoinhibited structure

Activated structure

5 structures for P35235

Entry ID	Method	Resolution	Chain	Position	Source
1AYA	X-ray	205 A	A/B	4-103	PDB
1AYB	X-ray	300 A	A	4-103	PDB
1AYC	X-ray	230 A	A	4-103	PDB
1AYD	X-ray	220 A	A	4-103	PDB
AF-P35235-F1	Predicted				AlphaFoldDB

1 variants for P35235

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
rs864285266	60	G>A		No	Ensembl

No associated diseases with P35235

6 regional properties for P35235

Type	Name	Position	InterPro Accession
domain	Tyrosine-specific protein phosphatase, PTPase domain	246 - 523	IPR000242
domain	Tyrosine-specific protein phosphatases domain	436 - 512	IPR000387
domain	SH2 domain	4 - 102	IPR000980-1
domain	SH2 domain	110 - 216	IPR000980-2
domain	Protein-tyrosine phosphatase, catalytic	414 - 520	IPR003595
active_site	Protein-tyrosine phosphatase, active site	457 - 467	IPR016130

Functions

		Description
EC Number	3.1.3.48	Phosphoric monoester hydrolases
Subcellular Localization	Cytoplasm
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category	No pathway information available

7 GO annotations of cellular component

Name	Definition
cytoplasm	The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.
cytosol	The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
mitochondrion	A semiautonomous, self replicating organelle that occurs in varying numbers, shapes, and sizes in the cytoplasm of virtually all eukaryotic cells. It is notably the site of tissue respiration.
nucleus	A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent.
plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.
plasma membrane raft	A membrane raft that is part of the plasma membrane.
protein-containing complex	A stable assembly of two or more macromolecules, i.e. proteins, nucleic acids, carbohydrates or lipids, in which at least one component is a protein and the constituent parts function together.

16 GO annotations of molecular function

Name	Definition
cadherin binding	Binding to cadherin, a type I membrane protein involved in cell adhesion.
cell adhesion molecule binding	Binding to a cell adhesion molecule.
D1 dopamine receptor binding	Binding to a D1 dopamine receptor.
insulin receptor binding	Binding to an insulin receptor.
insulin receptor substrate binding	Binding to an insulin receptor substrate (IRS) protein, an adaptor protein that bind to the transphosphorylated insulin and insulin-like growth factor receptors, are themselves phosphorylated and in turn recruit SH2 domain-containing signaling molecules to form a productive signaling complex.
non-membrane spanning protein tyrosine phosphatase activity	Catalysis of the reaction: non-membrane spanning protein tyrosine phosphate + H2O = non-membrane spanning protein tyrosine + phosphate.
peptide hormone receptor binding	Binding to a receptor for a peptide hormone.
phospholipase binding	Binding to a phospholipase.
phosphoprotein phosphatase activity	Catalysis of the reaction: a phosphoprotein + H2O = a protein + phosphate. Together with protein kinases, these enzymes control the state of phosphorylation of cellular proteins and thereby provide an important mechanism for regulating cellular activity.
phosphotyrosine residue binding	Binding to a phosphorylated tyrosine residue within a protein.
protein domain specific binding	Binding to a specific domain of a protein.
protein kinase binding	Binding to a protein kinase, any enzyme that catalyzes the transfer of a phosphate group, usually from ATP, to a protein substrate.
protein tyrosine kinase binding	Binding to protein tyrosine kinase.
protein tyrosine phosphatase activity	Catalysis of the reaction: protein tyrosine phosphate + H2O = protein tyrosine + phosphate.
receptor tyrosine kinase binding	Binding to a receptor that possesses protein tyrosine kinase activity.
signaling receptor complex adaptor activity	The binding activity of a molecule that provides a physical support for the assembly of a multiprotein receptor signaling complex.

57 GO annotations of biological process

Name	Definition
abortive mitotic cell cycle	A cell cycle in which mitosis is begun and progresses normally through the end of anaphase, but not completed, resulting in a cell with increased ploidy.
atrioventricular canal development	The progression of the atrioventricular canal over time, from its formation to the mature structure. The atrioventricular canal is the part of the heart connecting the atrium to the cardiac ventricle.
axonogenesis	De novo generation of a long process of a neuron, including the terminal branched region. Refers to the morphogenesis or creation of shape or form of the developing axon, which carries efferent (outgoing) action potentials from the cell body towards target cells.
Bergmann glial cell differentiation	The process in which neuroepithelial cells of the neural tube give rise to Brgmann glial cells, specialized bipotential progenitors cells of the cerebellum. Differentiation includes the processes involved in commitment of a cell to a specific fate.
brain development	The process whose specific outcome is the progression of the brain over time, from its formation to the mature structure. Brain development begins with patterning events in the neural tube and ends with the mature structure that is the center of thought and emotion. The brain is responsible for the coordination and control of bodily activities and the interpretation of information from the senses (sight, hearing, smell, etc.).
cellular response to epidermal growth factor stimulus	Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an epidermal growth factor stimulus.
cellular response to mechanical stimulus	Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a mechanical stimulus.
cerebellar cortex formation	The process that gives rise to the cerebellar cortex. This process pertains to the initial formation of a structure from unspecified parts. The cerebellar cortex is a thin mantle of gray matter that covers the surface of each cerebral hemisphere. It has a characteristic morphology with convolutions (gyri) and crevices (sulci) that have specific functions. Six layers of nerve cells and the nerve pathways that connect them comprise the cerebellar cortex. Together, these regions are responsible for the processes of conscious thought, perception, emotion and memory as well as advanced motor function.
DNA damage checkpoint signaling	A signal transduction process that contributes to a DNA damage checkpoint.
ephrin receptor signaling pathway	The series of molecular signals initiated by ephrin binding to its receptor, and ending with the regulation of a downstream cellular process, e.g. transcription.
epidermal growth factor receptor signaling pathway	The series of molecular signals initiated by binding of a ligand to the tyrosine kinase receptor EGFR (ERBB1) on the surface of a cell. The pathway ends with regulation of a downstream cellular process, e.g. transcription.
ERBB signaling pathway	The series of molecular signals initiated by binding of a ligand to a member of the ERBB family of receptor tyrosine kinases on the surface of a cell, and ending with the regulation of a downstream cellular process, e.g. transcription.
face morphogenesis	The process in which the anatomical structures of the face are generated and organized. The face is the ventral division of the head.
fibroblast growth factor receptor signaling pathway	The series of molecular signals generated as a consequence of a fibroblast growth factor receptor binding to one of its physiological ligands.
genitalia development	The process whose specific outcome is the progression of the genitalia over time, from its formation to the mature structure.
glucose homeostasis	Any process involved in the maintenance of an internal steady state of glucose within an organism or cell.
heart development	The process whose specific outcome is the progression of the heart over time, from its formation to the mature structure. The heart is a hollow, muscular organ, which, by contracting rhythmically, keeps up the circulation of the blood.
homeostasis of number of cells within a tissue	Any biological process involved in the maintenance of the steady-state number of cells within a population of cells in a tissue.
hormone metabolic process	The chemical reactions and pathways involving any hormone, naturally occurring substances secreted by specialized cells that affects the metabolism or behavior of other cells possessing functional receptors for the hormone.
hormone-mediated signaling pathway	The series of molecular signals mediated by the detection of a hormone.
inner ear development	The process whose specific outcome is the progression of the inner ear over time, from its formation to the mature structure.
integrin-mediated signaling pathway	The series of molecular signals initiated by an extracellular ligand binding to an integrin on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription.
intestinal epithelial cell migration	The orderly movement of an intestinal epithelial cell from one site to another, often during the development of a multicellular organism.
lipid metabolic process	The chemical reactions and pathways involving lipids, compounds soluble in an organic solvent but not, or sparingly, in an aqueous solvent. Includes fatty acids; neutral fats, other fatty-acid esters, and soaps; long-chain (fatty) alcohols and waxes; sphingoids and other long-chain bases; glycolipids, phospholipids and sphingolipids; and carotenes, polyprenols, sterols, terpenes and other isoprenoids.
megakaryocyte development	The process whose specific outcome is the progression of a megakaryocyte cell over time, from its formation to the mature structure. Megakaryocyte development does not include the steps involved in committing a cell to a megakaryocyte fate. A megakaryocyte is a giant cell 50 to 100 micron in diameter, with a greatly lobulated nucleus, found in the bone marrow.
microvillus organization	A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of a microvillus, a thin cylindrical membrane-covered projection on the surface of a cell.
multicellular organism growth	The increase in size or mass of an entire multicellular organism, as opposed to cell growth.
multicellular organismal reproductive process	The process, occurring above the cellular level, that is pertinent to the reproductive function of a multicellular organism. This includes the integrated processes at the level of tissues and organs.
negative regulation of cell adhesion mediated by integrin	Any process that stops, prevents, or reduces the frequency, rate, or extent of cell adhesion mediated by integrin.
negative regulation of chondrocyte differentiation	Any process that stops, prevents, or reduces the frequency, rate or extent of chondrocyte differentiation.
negative regulation of cortisol secretion	Any process that stops, prevents, or reduces the frequency, rate or extent of the regulated release of cortisol from a cell.
negative regulation of growth hormone secretion	Any process that decreases or stops the frequency, rate or extent of the regulated release of growth hormone from a cell.
negative regulation of hormone secretion	Any process that stops, prevents, or reduces the frequency, rate or extent of the regulated release of a hormone from a cell.
negative regulation of insulin secretion	Any process that stops, prevents, or reduces the frequency, rate or extent of the regulated release of insulin.
neurotrophin TRK receptor signaling pathway	The series of molecular signals initiated by neurotrophin binding to its receptor on the surface of a target cell where the receptor possesses tyrosine kinase activity, and ending with the regulation of a downstream cellular process, e.g. transcription.
organ growth	The increase in size or mass of an organ. Organs are commonly observed as visibly distinct structures, but may also exist as loosely associated clusters of cells that function together as to perform a specific function.
peptidyl-tyrosine dephosphorylation	The removal of phosphoric residues from peptidyl-O-phospho-tyrosine to form peptidyl-tyrosine.
platelet formation	The process in which platelets bud from long processes extended by megakaryocytes.
platelet-derived growth factor receptor signaling pathway	The series of molecular signals initiated by a ligand binding to a platelet-derived growth factor receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription.
positive regulation of ERK1 and ERK2 cascade	Any process that activates or increases the frequency, rate or extent of signal transduction mediated by the ERK1 and ERK2 cascade.
positive regulation of focal adhesion assembly	Any process that activates or increases the frequency, rate or extent of focal adhesion assembly, the establishment and maturation of focal adhesions.
positive regulation of glucose import	Any process that activates or increases the frequency, rate or extent of the import of the hexose monosaccharide glucose into a cell or organelle.
positive regulation of hormone secretion	Any process that activates or increases the frequency, rate or extent of the regulated release of a hormone from a cell.
positive regulation of insulin receptor signaling pathway	Any process that increases the frequency, rate or extent of insulin receptor signaling.
positive regulation of interferon-beta production	Any process that activates or increases the frequency, rate, or extent of interferon-beta production.
positive regulation of interleukin-6 production	Any process that activates or increases the frequency, rate, or extent of interleukin-6 production.
positive regulation of mitotic cell cycle	Any process that activates or increases the rate or extent of progression through the mitotic cell cycle.
positive regulation of ossification	Any process that activates or increases the frequency, rate or extent of ossification, the formation of bone or of a bony substance or the conversion of fibrous tissue or of cartilage into bone or a bony substance.
positive regulation of peptidyl-tyrosine phosphorylation	Any process that activates or increases the frequency, rate or extent of the phosphorylation of peptidyl-tyrosine.
positive regulation of signal transduction	Any process that activates or increases the frequency, rate or extent of signal transduction.
positive regulation of tumor necrosis factor production	Any process that activates or increases the frequency, rate or extent of tumor necrosis factor production.
protein dephosphorylation	The process of removing one or more phosphoric residues from a protein.
regulation of cell adhesion mediated by integrin	Any process that modulates the frequency, rate, or extent of cell adhesion mediated by integrin.
regulation of MAPK cascade	Any process that modulates the frequency, rate or extent of signal transduction mediated by the MAP kinase (MAPK) cascade.
regulation of protein export from nucleus	Any process that modulates the frequency, rate or extent of the directed movement of proteins from the nucleus to the cytoplasm.
regulation of protein-containing complex assembly	Any process that modulates the frequency, rate or extent of protein complex assembly.
triglyceride metabolic process	The chemical reactions and pathways involving triglyceride, any triester of glycerol. The three fatty acid residues may all be the same or differ in any permutation. Triglycerides are important components of plant oils, animal fats and animal plasma lipoproteins.

7 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
Q90687	PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Gallus gallus (Chicken)	SS
P29350	PTPN6	Tyrosine-protein phosphatase non-receptor type 6	Homo sapiens (Human)	EV
Q06124	PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Homo sapiens (Human)	EV
P29351	Ptpn6	Tyrosine-protein phosphatase non-receptor type 6	Mus musculus (Mouse)	SS
P81718	Ptpn6	Tyrosine-protein phosphatase non-receptor type 6	Rattus norvegicus (Rat)	SS
P41499	Ptpn11	Tyrosine-protein phosphatase non-receptor type 11	Rattus norvegicus (Rat)	SS
G5EC24	ptp-2	Tyrosine-protein phosphatase non-receptor type ptp-2	Caenorhabditis elegans	SS

10	20	30	40	50	60
MTSRRWFHPN	ITGVEAENLL	LTRGVDGSFL	ARPSKSNPGD	FTLSVRRNGA	VTHIKIQNTG
70	80	90	100	110	120
DYYDLYGGEK	FATLAELVQY	YMEHHGQLKE	KNGDVIELKY	PLNCADPTSE	RWFHGHLSGK
130	140	150	160	170	180
EAEKLLTEKG	KHGSFLVRES	QSHPGDFVLS	VRTGDDKGES	NDGKSKVTHV	MIRCQELKYD
190	200	210	220	230	240
VGGGERFDSL	TDLVEHYKKN	PMVETLGTVL	QLKQPLNTTR	INAAEIESRV	RELSKLAETT
250	260	270	280	290	300
DKVKQGFWEE	FETLQQQECK	LLYSRKEGQR	QENKNKNRYK	NILPFDHTRV	VLHDGDPNEP
310	320	330	340	350	360
VSDYINANII	MPEFETKCNN	SKPKKSYIAT	QGCLQNTVND	FWRMVFQENS	RVIVMTTKEV
370	380	390	400	410	420
ERGKSKCVKY	WPDEYALKEY	GVMRVRNVKE	SAAHDYTLRE	LKLSKVGQGN	TERTVWQYHF
430	440	450	460	470	480
RTWPDHGVPS	DPGGVLDFLE	EVHHKQESIV	DAGPVVVHCS	AGIGRTGTFI	VIDILIDIIR
490	500	510	520	530	540
EKGVDCDIDV	PKTIQMVRSQ	RSGMVQTEAQ	YRFIYMAVQH	YIETLQRRIE	EEQKSKRKGH
550	560	570	580	590
EYTNIKYSLV	DQTSGDQSPL	PPCTPTPPCA	EMREDSARVY	ENVGLMQQQR	SFR