This entry represents the magnesium-dependent bifunctional phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase/dual-specificity protein phosphatase PTEN (; ; ), which possesses the following catalytic activities:Phosphatidylinositol 3,4,5-trisphosphate + H(2)O = phosphatidylinositol 4,5-bisphosphate + phosphate.A phosphoprotein + H(2)O = a protein + phosphate.Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.This protein acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins []. It also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate. The lipid phosphatase activity is critical for its tumour suppressor function []. PTEN antagonizes the PI3K-AKT/PKB signalling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form of PTEN cooperates with AIP1 to suppress AKT1 activation. PTEN dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion form [].
This entry represents the phosphatase domain found in PTEN, which is a magnesium-dependent bifunctional phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase/dual-specificity protein phosphatase PTEN (; ; ), which possesses the following catalytic activities:Phosphatidylinositol 3,4,5-trisphosphate + H(2)O = phosphatidylinositol 4,5-bisphosphate + phosphate.A phosphoprotein + H(2)O = a protein + phosphate.Protein tyrosine phosphate + H(2)O = protein tyrosine + phosphate.This protein acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins []. It also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate. The lipid phosphatase activity is critical for its tumour suppressor function []. PTEN antagonizes the PI3K-AKT/PKB signalling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form of PTEN cooperates with AIP1 to suppress AKT1 activation. PTEN dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion form [].
Formins (formin homology proteins) proteins play a crucial role in the reorganisation of the actin cytoskeleton and associate with the fast-growing end (barbed end) of actin filaments [, ]. This entry represents the formin homologues from plants. Seed plants have two formin clades with numerous paralogues []. They can be classified as class I and class II formins. Class I formins includes a N-terminal membrane insertion signal, a predicted extracytoplasmic Pro-rich stretch, a transmembrane region, and C-terminal FH1 and FH2 domains []. Though class II formins usually contain a N-terminal PTEN domain related to the human PTEN protein (implied in pathogenesis of the Parkinson disease) [], the N-termini of type-II plant formins do not contain any recognisable domain that can provide a clue to their biological function.
Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI2) is a scaffold protein that recruits various proteins via its PDZ domains at cell-cell junctions. The interaction between delta2 glutamate receptor and MAGI2 may be important for intracellular trafficking of the receptor []. MAGI2 regulates the PTEN signalling through the assembly of a multiprotein complex at the cell membrane []. It is one of the binding partners for the oncoprotein E6 of the HPVs (high-risk type human papillomaviruses) [].
This entry represents the SH2 domain found in tensin-like proteins. The tensins are a family of intracellular proteins that interact with receptor tyrosine kinases (RTKs), integrins, and actin. They are thought act as signaling bridges between the extracellular space and the cytoskeleton. There are four homologues: tensin1, tensin2 (TENC1, C1-TEN), tensin3 and tensin4 (cten), all of which contain a C-terminal tandem SH2-PTB domain pairing, as well as actin-binding regions that may localize them to focal adhesions. The isoforms of tensin2 and tensin3 contain N-terminal C1 domains, which are atypical and not expected to bind to phorbol esters. Tensins 1-3 contain a phosphatase (PTPase) and C2 domain pairing which resembles PTEN (phosphatase and tensin homologue deleted on chromosome 10) protein [].PTEN is a lipid phosphatase that dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to yield phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). As PtdIns(3,4,5)P3 is the product of phosphatidylinositol 3-kinase (PI3K) activity, PTEN is therefore a key negative regulator of the PI3K pathway []. Because of their PTEN-like domains, the tensins may also possess phosphoinositide-binding or phosphatase capabilities. However, only tensin2 and tensin3 have the potential to be phosphatases since only their PTPase domains contain a cysteine residue that is essential for catalytic activity. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , ].
Frk (RAK) is a member of the Src non-receptor type tyrosine kinase family of proteins. The Frk subfamily is composed of Frk/Rak and Iyk/Bsk/Gst. It is expressed primarily epithelial cells. Frk is a nuclear protein and may function during G1 and S phase of the cell cycle and suppress growth []. Unlike the other Src members it lacks a glycine at position 2 of SH4 which is important for addition of a myristic acid moiety that is involved in targeting Src PTKs to cellular membranes []. FRK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where both induce PC12 cell differentiation and beta-cell proliferation. Under conditions that cause beta-cell degeneration these proteins augment beta-cell apoptosis. The FRK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2 []. Frk has been demonstrated to interact with retinoblastoma protein []. Frk regulates PTEN protein stability by phosphorylating PTEN, which in turn prevents PTEN degradation []. Frk also plays a role in regulation of embryonal pancreatic beta cell formation [].The Src non-receptor type tyrosine kinase (SFK) family members have an unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail. The SH2 domain of SFKs is involved in kinase autoinhibition and T-cell receptor signaling. The binding SH2 domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the SFKs [].
Tensins constitute an eukaryotic family of lipid phosphatases that are defined by thepresence of two adjacent domains: a lipid phosphatase domain and a C2-like domain. The tensin-type C2 domain has a structure similar to the classical C2 domain (see ) that mediates the Ca2+-dependent membrane recruitment of several signalling proteins. However the tensin-type C2 domain lacks two of the three conserved loops that bind Ca2+, and in this respect it is similar to the C2 domains of PKC-type [, ]. The tensin-type C2 domain can bind phopholipid membranes in a Ca2+ independent manner []. In the tumour suppressor protein PTEN, the best characterised member of the family, the lipid phosphatase domain was shown to specifically dephosphorylate the D3 position of the inositol ring of the lipid second messenger, phosphatydilinositol-3-4-5-triphosphate (PIP3). The lipid phosphatase domain contains the signature motif HCXXGXXR present in the active sites of protein tyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs). Furthermore, two invariant lysines are found only in the tensin-type phosphatase motif (HCKXGKXR) and are suspected to interact with the phosphate group at position D1 and D5 of the inositol ring [, ]. The C2 domain is found at the C terminus of the tumour suppressor protein PTEN (phosphatidyl-inositol triphosphate phosphatase). This domain may include a CBR3 loop, indicating a central role in membrane binding. This domain associates across an extensive interface with the N-terminal phosphatase domain DSPc suggesting that the C2 domain productively positions the catalytic part of the protein on the membrane. The crystal structure of the PTEN tumour suppressor has been solved []. The lipid phosphatase domain has a structure similar to the dual specificity phosphatase (see ). However, PTEN has a larger active site pocket that could be important to accommodate PI(3,4,5)P3. Proteins known to contain a phosphatase and a C2 tensin-type domain are listed below: Tensin, a focal-adhesion molecule that binds to actin filaments. It may be involved in cell migration, cartilage development and in linking signal transduction pathways to the cytoskeleton.Phosphatase and tensin homologue deleted on chromosome 10 protein (PTEN). It antagonizes PI 3-kinase signalling by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P3 and thus inactivates downstream signalling. It plays major roles both during development and in the adult to control cell size, growth, and survival.Auxilin. It binds clathrin heavy chain and promotes its assembly into regular cages.Cyclin G-associated kinase or auxilin-2. It is a potential regulator of clathrin-mediated membrane trafficking.
MAST (Microtubule-Associated Serine/Threonine) kinases are characterised by containing a serine/threonine kinase domain and a PDZ (postsynaptic density protein-95/discs large/zona occludens-1) domain []. There are four mammalian MAST kinases, named MAST1-MAST4. MAST1, MAST2, and MAST3 bind and phosphorylate the tumor suppressor PTEN, and may contribute to the regulation and stabilization of PTEN []. MAST1 links the dystrophin/utrophin network with microtubule filaments via the syntrophins []. MAST1 localises in the DAPC/UAPC, which is found within the postsynaptic region of the neuromuscular junction (NMJ) and central synapses []. The splice variant of its C-terminal affects its subcellular localisation within neurons []. MAST2 is involved in the regulation of the Fc-gamma receptor of the innate immune response in macrophages, and may also be involved in the regulation of the Na+/H+ exchanger NHE3 [].
The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) of tensin tends to be found at the C terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 () domain and a region similar to the tumour suppressor PTEN []. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif []. The PTB domain is also found in the epidermal growth factor receptor kinase substrate 8 (EPS8).PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains [].This entry refers to the PTB domain found in Tensin, part of the Dab-like subgroup.
Tensins constitute an eukaryotic family of lipid phosphatases that are definedby the presence of two adjacent domains: a lipid phosphatase domain and aC2-like domain. The tensin-type C2 lacks the canonical Ca(2+) ligands found inclassical C2 domains, and in this respect it is similar tothe C2 domains of PKC-type [, ]. The tensin-type C2 domain can bindphospholipid membranes in a Ca(2+) independent manner []. In the tumorsuppressor protein PTEN, the best characterized member of the family, thelipid phosphatase domain was shown to specifically dephosphorylate the D3position of the inositol ring of the lipid second messenger,phosphatydilinositol-3-4-5-triphosphate (PIP3). The lipid phosphatase domaincontains the signature motif HCXXGXXR present in the active sites of proteintyrosine phosphatases (PTPs) and dual specificity phosphatases (DSPs).Furthermore, two invariant lysines are found only in the tensin-typephosphatase motif (HCKXGKXR) and are suspected to interact with the phosphategroup at position D1 and D5 of the inositol ring [, ].The crystal structure of the PTEN tumor suppressor has been solved []. The lipid phosphatase domain has a structure similar to thedual specificity phosphatase. However, PTEN has a largeractive site pocket that could be important to accomodate PI(3,4,5)P3. Thetensin-type C2 domain has a structure similar to the classical C2 domain thatmediates the Ca2+ dependent membrane recruitment of several signalingproteins. However the tensin-type C2 domain lacks two of the three conservedloops that bind Ca2+.Proteins known to contain a phosphatase and a C2 tensin-type domain are listed below:Tensin, a focal-adhesion molecule that binds to actin filaments. It may beinvolved in cell migration, cartilage development and in linking signaltransduction pathways to the cytoskeleton.Phosphatase and tensin homologue deleted on chromosome 10 protein (PTEN).It antagonizes PI 3-kinase signalling by dephosphorylating the 3-positionof the inositol ring of PI(3,4,5)P3 and thus inactivates downstreamsignalling. It plays major roles both during development and in the adultto control cell size, growth, and survival.Auxilin. It binds clathrin heavy chain and promotes its assembly intoregular cages.Cyclin G-associated kinase or auxilin-2. It is a potential regulator ofclathrin-mediated membrane trafficking.PTEN homologues in fungi have the tensin phosphatase domain, but they lack the C2 domain. .This entry represents the phosphatase domain.
Proteins containing this domain are a family of phosphoinositide phosphatases with substrates that include phosphatidylinositol-4,5-diphosphate and phosphatidylinositol-3,4,5-trisphosphate. This family is conserved in deuterostomes; VSP was first identified as a sperm flagellar plasma membrane protein in Ciona intestinalis []. Gene duplication events in primates resulted in the presence of paralogs, transmembrane phosphatase with tensin homology (TPTE) and TPTE2, that retain protein domain architecture but, in the case of TPTE, have lost catalytic activity. TPTE, also called cancer/testis antigen 44 (CT44), may play a role in the signal transduction pathways of the endocrine or spermatogenic function of the testis. TPTE2, also called TPTE and PTEN homologous inositol lipid phosphatase (TPIP), occurs in several differentially spliced forms; TPIP alpha displays phosphoinositide 3-phosphatase activity and is localized on the endoplasmic reticulum, while TPIP beta is cytosolic and lacks detectable phosphatase activity [, ]. VSP/TPTE proteins contain an N-terminal voltage sensor consisting of four transmembrane segments, a protein tyrosine phosphatase (PTP)-like phosphoinositide phosphatase catalytic domain, followed by a regulatory C2 domain [].
The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) of tensin tends to be found at the C terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 () domain and a region similar to the tumour suppressor PTEN []. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif []. The PTB domain is also found in the epidermal growth factor receptor kinase substrate 8 (EPS8).PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules []. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether []. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine []. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains [].
This superfamily represents a domain found in some protein-tyrosine phosphatases, including dual specificity phosphatases, myotubularin-like phosphatases [], receptor-type tyrosine-protein phosphatases and non receptor-type tyrosine-protein phosphatases. This domain also shares structure similarity with the lipid phosphatase domain in tensin []and tensin like proteins, such as cyclin G-associated kinase (GAK) []and phoshphoinositide phosphatase PTEN (phosphatase and tensin homologue) [].Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase; ) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation [, ]. The PTP superfamily can be divided into four subfamilies []:(1) pTyr-specific phosphatases(2) dual specificity phosphatases (dTyr and dSer/dThr)(3) Cdc25 phosphatases (dTyr and/or dThr)(4) LMW (low molecular weight) phosphatasesBased on their cellular localisation, PTPases are also classified as:Receptor-like, which are transmembrane receptors that contain PTPase domains []Non-receptor (intracellular) PTPases []All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif []. Functional diversity between PTPases is endowed by regulatory domains and subunits.
