Receptor-like protein tyrosine phosphatases

Receptor-like protein tyrosine phosphatases Receptor tyrosine kinases Stress-activated PK/cJun N-terminal kinase SAPK/ERK kinase 1 Src homology domain 2 Transforming growth factor-(3 Tumour necrosis factor 12-O-tetradecanoylphorbol-13-acetate Tyrosine specific phosphatases... 

FIGURE 24-10 Schematic structures of nonreceptor protein tyrosine phosphatases (NRPTPs) and receptor protein tyrosine phosphatases (RPTPs). NRPTPs contain a catalytic domain and various regulatory domains. RPTPs are composed of an extracellular domain, a transmembrane domain and an intracellular domain with one or two catalytic domains. Like receptor protein tyrosine kinases, the structural features of the extracellular domains divide the RPTPs into different families. (With permission from reference [12]). 

The receptor-like protein tyrosine phosphatases have a transmembrane and, in some cases, a large extracellular domain with a very variable structme (Fig. 8.16). Many, but not all, membrane protein tyrosine phosphatases have two catalytic domains in the cytoplasmic region. The complete structme is very similar to the structure of transmembrane receptors. Understanding of their function is far from complete. Both the natural ligands and the substrate proteins following in the sequence are incompletely characterized. Several studies have demonstrated a role for receptor-like PTPs in neuronal cell adhesion signaling pathways. In cells of the neural tissue, a surface protein, contactin has been identified as ligand for the extracellular domain of a protein tyrosine phosphatase (Peles et al., 1995). 

Signal transduction via the receptor-like CD 45 protein tyrosine phosphatase in cells of the blood forming system requires its intracellularly localized phosphatase activity. The cytoplasmic tyrosine kinases p56 " and p59 are thought to be cellular substrates... 

Fig. 3.8 The protein tyrosine phosphatases (PTPs) with the C(X)gR motif are divided into tyrosine-specific PTPs the VHl-like dual specificity, serine/threonine- and tyrosine-specific phosphatases the CDC25 phosphatase and the low molecular weight (LMW) phosphatases. The low molecular weight phosphatases are acid phosphatases without distinct regulatory or targeting domains. Their function is not known. The tyosiiie-speoifio phosphatases are further subdivided into receptor-like and non-reoeptor-like phosphatases. (This scheme is reproduced with permission of the authors and Trends Biochem. Sci. from ref. 76.)...

RPTPs = Receptor-like protein tyrosine phosphatases... 

Streuli M, Krueger NX, Thai T et al (1990) Distinct functional roles of the two intracellular phosphatase like domains of the receptor-linked protein tyrosine phosphatases LCA and LAR. EMBO J 9 2399-2407... 

Pot DA, Dixon JE (1992) Active site labeling of a receptor-like protein tyrosine phosphatase. J Biol Chem 267 140-143... 

Fig. 8.22 Regulation of protein tyrosine phosphatases (PTPs). The specific activity of PTPs can be either increased or decreased by phosphorylation of serine, threonine or tyrosine residues. Reversible or irreversible oxidation of the active-site cysteine residue (denoted C) also inactivates PTPs. For receptor-like PTPs (RPTPs), dimerization of the catalytic domains has also been proposed as an inhibitory regulatory mechanism. Furthermore, ligand binding to the extracellular domains has been proposed as an inhibitory mechanism. Modulation of specific activity following ligand binding could involve changes in the phosphorylation, oxidation state of the active-site cysteine or dimerization.

Fig. 4. The domain organizations of some CUE and LIP domain-containing proteins. Yeast Der3p/Hrdlp and Cuelp are proteins of the endoplasmic reticulum degradation pathway. As human autocrine motility factor receptor (AMFR) contains the same domain organization of a conceptual Der3p/Hrdlp and Cuelp fusion, it is proposed that DerSp/Hrdlp and Cuelp interact physically (Pouting, 2000). The C. elegans sequence most similar to human Tollip contains a C-terminal extension containing an F-box domain and an incomplete LIP domain. Over 190 LIP domains occur in at least 172 C. elegans hypothetical proteins, but have not been observed in other species sequences the functions of this domain remain unknown. LIP domains frequently co-occur with F-box domains and in one case (C33F10.8) a protein tyrosine phosphatase-like (FTP) domain.

Protein tyrosine phosphatases. Phosphoprotein phosphatases are integral components of the signahng systems operated by protein kinases (Sun and Tonks, 1994). Cloning data show the protein tyrosine phosphatases (PTPs) to be a family of multidomain proteins having exceptional diversity. They can be broadly divided into two groups, the transmembrane or receptor-like PTPs and the cytosolic PTPs. None of these are related to the serine-threonine specific phosphatases. This is in contrast to the protein kinases (Seer-Thr and Tyr specific), which share a common ancestry. Unlike the Ser-Thr phosphatases, in which substrate specificity is determined by associated targeting subunits, the Tyr phosphatases are all monomeric enzymes. 

Blery M, Kubagawa H, Chen CC, Vely F, Cooper MD, Vivier E (1998) The paired Ig-like receptor PIR-B is an inhibitory receptor that recruits the protein-tyrosine phosphatase SHP-1. Proc Natl Acad Sci USA 95 2446-2451... 

Hamanaka, H., N. Maeda, and M. Noda. 1997. Spatially and temporally regulated modification of the receptor-like protein tyrosine phosphatase /P isoforms with keratan sulphate in the developing chick brain. Eur. J. Neurosci 9 2297-2308. 

Fig. 11. Modes of action of fluorine on osteoblastic cells, (a) Tyrosine phosphatase hypothesis in osteoblastic cells, fluoride ion directly inhibits tyrosine phosphatase. Inhibition of this enzyme enhances the tyrosine phosphorylation of signalling molecules induced by receptor tyrosine kinase, which leads to activation of the extracellular signal-regulated kinase (ERK) through the Ras pathway and enhanced cell proliferation, (b) G-protein hypothesis in osteoblast-like cells, fluoride ions form a complex with aluminum, probably fluoroaluminate, which interacts with guanosine 5 -diphosphate (GDP) to form guanosine 5 -triphosphate (GTP)-like molecule. Activation of the G, protein stimulates the tyrosine phosphorylation of signalling molecules by a yet unknown tyrosine kinase (Tyr Kin) and activation of the ERK kinase through the Ras pathway leads to enhanced cell proliferation. (Reproduced by permission of Elsevier from Ref. [175] ...

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