Transmembrane protein tyrosine phosphatases

Serra-Pages C, Medley QG, Tang M, Hart A, Streuli M (1998) Liprins, a family of LAR transmembrane protein-tyrosine phosphatase-interacting proteins. J Biol Chem 275 15611-15620. 

Receptor protein tyrosine phosphatases consist of an extracellular domain, a transmembrane domain and one or two intracellular catalytic domains 426... 

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]). 

Fig. 5.5. General functions of transmembrane receptors. Extracellular signals convert the transmembrane receptor from the inactive form R to the active form R. The activated receptor transmits the signal to effector proteins next in the reaction sequence. Important effector reactions are the activation of heterotrimeric G-proteins, of protein tyrosine kinases and of protein tyrosine phosphatases. The tyrosine kinases and tyrosine phosphatases may be an intrinsic part of the receptor or they may be associated with the receptor. The activated receptor may also include adaptor proteins in the signaling pathway or it may induce opening of ion channels.

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). 

Fig. 8.16. Domain structure of protein tyrosine phosphatases. Linear representation of functional domains of the transmembrane tyrosine phosphatase CD45 and some cytoplasmic tyrosine phosphatases.

Fischer, E.H., Charbonneau, H. and Tonks, N.K. Protein tyrosine phosphatases a diverse famUiy of intraceUnlar and transmembrane enzymes Sdence (1991) 253, 401-406... 

E. H. Fischer, H. Charbonneau, and N. K. Tonks. Protein tyrosine phosphatases a diverse family of intracellular and transmembrane enzymes. Science, 253 401-406, 1991. 

Many members of this class of receptors have an enzymatic activity known as a protein tyrosine kinase within their cytoplasmic segment. This kinase phosphorylates tyrosine residues in the receptors themselves (autophosphory lation), and in other proteins to initiate biochemical cascades. Phosphorylatipn of tyrosine can be reversed by protein tyrosine phosphatases, which are also present in all cells (Shenolikar and Naim, 1990). Tyrosine phosphatases form a diverse family of proteins, some of which are cytosolic while others are transmembrane molecules analogous to receptors. Some members of the transmembrane class may be involved in the mechanism of bacterial and viral infections (Tonks, 1991). Thus, kinases and phosphatases together act as on-off switches in the a ctivation of receptors and other proteins. 

Some transmembrane receptors have cytoplasmic protein phosphatase activity. Soluble protein phosphatases, such as calcineurin, PP1, PP2A, PP2C, and protein tyrosine phosphatases, also mediate intracellular signals. 

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. 

Receptor Serine/Threonine Receptor Protein Kinase = Receptor Protein Phosphotyrosine Phosphatase = Receptor Tyrosine Kinase = Signal Transducer and Activator of Transcription = Transforming Growth Factor P = Tetradecanoylphorbolacetate = Tetradecanoylphorbolacetate Response Element = Change in Permeability of PM to specific solutes = Change in Transmembrane Potential. 

Some proteins, such as transmembrane and intracellular tyrosine phosphatases, important in signal transduction and needing to be regulated, have sequences outside the catalytic domain that serve as zip codes and direct the protein to the correct address [193]. 

Myristic acid may be linked via an amide bond to the a-amino group of the N-terminal glycine residue of selected proteins (Figure 9.18). The reaction is referred to as A -myristoylation and is catalyzed by myristoyl—CoAtprolein N-myris-toyltransferase, known simply as NMT. A -Myristoyl-anchored proteins include the catalytic subunit of cAMP-dependent protein kinase, the ppSff tyrosine kinase, the phosphatase known as calcineurin B, the a-subunit of G proteins (involved in GTP-dependent transmembrane signaling events), and the gag proteins of certain retroviruses, including the FHV-l virus that causes AIDS. 

Receptor tyrosine kinases are integral membrane proteins that have a hgand-binding domain on the extracellular side and a tyrosine kinase domain on the cytosohc side (see Fig. 8.1). The transmembrane portion is made up of just one structural element thus it is assumed that it crosses the membrane in an a-hehcal form. On the cytoplasmic side, in addition to the conserved tyrosine kinase domain, there are also further regulatory sequence portions at which autophosphorylation, and phosphorylation and dephosphorylation by other protein kinases and by protein phosphatases, can take place. 

---