Protein tyrosine phosphatases in glioma biology

Abstract

Gliomas are a diverse group of brain tumors of glial origin. Most are characterized by diffuse infiltrative growth in the surrounding brain. In combination with their refractive nature to chemotherapy this makes it almost impossible to cure patients using combinations of conventional therapeutic strategies. The drastically increased knowledge about the molecular underpinnings of gliomas during the last decade has elicited high expectations for a more rational and effective therapy for these tumors. Most studies on the molecular pathways involved in glioma biology thus far had a strong focus on growth factor receptor protein tyrosine kinase (PTK) and phosphatidylinositol phosphatase signaling pathways. Except for the tumor suppressor PTEN, much less attention has been paid to the PTK counterparts, the protein tyrosine phosphatase (PTP) superfamily, in gliomas. PTPs are instrumental in the reversible phosphorylation of tyrosine residues and have emerged as important regulators of signaling pathways that are linked to various developmental and disease-related processes. Here, we provide an overview of the current knowledge on PTP involvement in gliomagenesis. So far, the data point to the potential implication of receptor-type (RPTPdelta, DEP1, RPTPmicro, RPTPzeta) and intracellular (PTP1B, TCPTP, SHP2, PTPN13) classical PTPs, dual-specific PTPs (MKP-1, VHP, PRL-3, KAP, PTEN) and the CDC25B and CDC25C PTPs in glioma biology. Like PTKs, these PTPs may represent promising targets for the development of novel diagnostic and therapeutic strategies in the treatment of high-grade gliomas.

Fig. 1

Reversibility of signaling pathways by virtue of protein tyrosine phosphatase activity. The opposing actions of PTK and protein tyrosine phosphatase (PTP) enzymes provide the cell with a functional diad that regulates the activity of the mutual substrates through phosphorylation of tyrosine (Y) residues in a reversible manner. Note that phosphorylation itself may well regulate the activity of PTKs and PTPs themselves. Therefore, PTPs do not simply repress or undo PTK activity; they may synergize or cooperate in situations where tyrosine phosphorylation boosts PTP activity or dephosphorylation activates the PTK. Some PTPs have a so-called dual specificity; in addition to their activity towards phosphotyrosine they are also able to dephosphorylate serine (S) and/or threonine (T) residues in protein substrates that have been phosphorylated by serine/threonine kinases (S/T-K). A subset of these dual-specific PTPs, most notably the tumor suppressor protein PTEN, even demonstrate the potential to dephosphorylate phospholipid substrates like phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) that is produced by phosphatidylinositol-3-kinase (PI3K)-mediated phosphorylation of PtdIns(4,5)P2 (phosphatidylinositol-4,5-bisphosphate)

Fig. 2

Interplay of PTP signaling and the major pathways affected in glioblastomas. The Ras/PI3K, p53 and Rb signaling pathways, which are often altered in glioblastomas, are shown in a cellular context. For simplicity, only major factors that are described in the text are depicted. Proteins shown in vermillion are frequently hyperactive in gliomas (due to amplification/mutation) while proteins in blue are frequently hypoactive or even inactive (as a result of mutation/deletion). The (mostly green) asterisks represent the receptor-type and non-transmembrane PTPs (protein names are used) that are discussed in the text and in Table 1, and the ways how they feed into the Ras/PI3K, p53 and Rb pathways and affect cellular processes (boxed text) is depicted. Arrows indicate interactions that result in stimulation, lines ending with a perpendicular bar indicate inhibitory interactions. Dashed lines reflect indirect interaction pathways. PIP2 phosphatidylinositol-4,5-bisphosphate, PIP3 phosphatidylinositol-3,4,5-triphosphate

Fig. 3

Domain structure of the PTP superfamily members implicated in glioma biology. Schematic representations of class I transmembrane receptor type and intracellular ‘classical’ PTPs are given in the upper and middle part of the figure, respectively. The lower part shows the class I dual-specific phosphatases and the class III CDC25 family members. Thus far, class II and class IV type PTPs have not been implicated in gliomagenesis. Alternative splicing of genes PTPRZ and PTPN2 leads to expression of three variants of RPTPζ [87] and two of TCPTP [60], respectively. PTP protein names are used here (Table 1), and isoform names are in italics. Protein domain names and acronyms are indicated and the curly tail in PRL-3 represents its C-terminal prenylation. CA carbonic anhydrase-like domain, FERM band 4.1/ezrin/radixin/moesin homology domain, FNIII fibronectin type III repeat, Glyc glycosylation sites encoded within PTPRZ exon 12, Ig immunoglobulin-like repeat, KIND kinase non-catalytic C-lobe domain, MA membrane-associated domain, MAM meprin/A5-protein/PTPμ homology domain, PDZ PSD-95/discs-large/ZO-1 homology domain, PTP catalytic protein tyrosine phosphatase domain, SH2 Src homology 2 domain, TM transmembrane domain. Drawings are to scale (bar corresponds to 500 amino acid residues)