Elsevier

Cellular Signalling

Volume 17, Issue 11, November 2005, Pages 1323-1332
Cellular Signalling

Review
A SHPing tale: Perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail

https://doi.org/10.1016/j.cellsig.2005.05.016Get rights and content

Abstract

Protein tyrosine phosphorylation is a ubiquitous signalling mechanism and is regulated by a balance between the action of kinases and phosphatases. The SH2 domain-containing phosphatases SHP-1 and SHP-2 are the best studied of the classical non-receptor tyrosine phosphatases, but it is intriguing that despite their close sequence and structural homology these two phosphatases play quite different cellular roles. In particular, whereas SHP-1 plays a largely negative signalling role suppressing cellular activation, SHP-2 plays a largely positive signalling role. Major sequence differences between the two molecules are apparent in the approximately 100 amino acid residues at the extreme C-terminus of the proteins, beyond the phosphatase catalytic domain. Here we review how the differences in the tails of these proteins may regulate their activities and explain some of their functional differences.

Introduction

It is widely accepted that the reversible modification of tyrosine residues within proteins is determined by a balance between the opposing activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The recent elucidation of the human genome sequence together with comprehensive analysis, using the amino acid sequences of conserved catalytic motifs and whole catalytic domains of all previously known PTPs, revealed the presence of 107 genes [1], [2]. However, of these 107 genes only 81 are likely to encode proteins that dephosphorylate phosphotyrosine [2], which is similar to the number (85) of catalytically active PTKs in the human genome. The 107 PTP genes have been subdivided into four families based upon similarity of their catalytic domains [2] and this classification is summarised in Fig. 1. The 38 classical PTPs, characterised by the V/I-H-C-S-X-G motif within their catalytic domains, are strictly phosphotyrosine-specific. Classical PTPs, henceforth simply PTPs, are subdivided still further into the receptor-like PTPs (rPTPs) and the non-receptor-like, or cytosolic PTPs (nrPTPs). The receptor-like PTPs contain a membrane-spanning region, an extracellular region of varying size that in most cases contains structural domains and a cytosolic region that in the majority of cases contains two catalytic domains although only one of these is catalytically active. The majority of cytosolic PTPs have a multidomain structure in which accessory modules, e.g. PDZ, FERM, Pro-rich and SH2 domains, have been added to the catalytic domain. These accessory modules are presumed to perform important targeting functions directing the catalytic domain to precise locations and protein complexes within the cell where their substrates and regulatory proteins reside. Of all the active PTPs within the genome only two cytosolic PTPs, SHP-1 and SHP-2, contain tandem SH2 domains, although two others within the PTEN family also contain a single SH2 domain (tensin and C1-ten). In fact both SHP-1 and SHP-2 contain two tandem SH2 domains positioned at the N-terminus of the molecule, followed by the catalytic domain and a C-terminal tail. The C-terminal tail of these enzymes contains multiple sites of tyrosine and serine phosphorylation and this region of the molecule has been proposed to have an important regulatory function and is the subject of this review.

Section snippets

The SH2 domain-containing tyrosine phosphatases

There are five known isoforms of the SH2 domain-containing tyrosine phosphatases: 4 isoforms of SHP-1 and 1 isoform of SHP-2 (Fig. 1). There is a haematopoietic cell-specific isoform of SHP-1 and a non-haematopoietic cell isoform of SHP-1 that arise due to usage of alternative initiation sites and vary by 3 amino acids at the N-terminus [3]. A 70 kDa form of SHP-1, SHP-1L, has also been identified [4]. This isoform is longer than SHP-1 and differs by 66 amino acids at the C-terminus due to

The role of the SH2 domains in regulating SHP1 / 2 function

The crystal structures of C-terminally truncated forms of both SHP-1 [18] and SHP-2 [19] have been solved and they immediately reveal a role for the N-terminal SH2 domain in regulating the phosphatase activity of the enzyme. In the ‘closed’ inhibited form, the N-terminal SH2 domain forms extensive contacts with the catalytic domain through charge–charge interactions. The C-terminal SH2 domain has little interaction with the N-terminal SH2 domain or the catalytic domain except through the

The role of the C-terminus in regulating SHP1/2 function

It is clear that the C-termini of SHPs are important for their function. First, it is in this region of the molecules where the greatest degree of sequence divergence occurs, and therefore it is in these regions of the molecules where the different functional characteristics of these phosphatases may lie. Second, various truncation deletion experiments have highlighted the importance of this region. Pei et al. (1994) showed that truncation of the last 35 amino acids of SHP-1 markedly enhanced

Future perspectives

SHP-1 and SHP-2 are highly homologous, especially within regions outside of their C-termini, and a key question therefore remains as to how the two molecules play such distinct and often opposing cellular roles. It is likely that some of the answers lie in their differential regulation by their C-termini, which differ markedly from each other in several respects reviewed here. Although there is now a wealth of information regarding the regulation and role of SHP-1 and SHP-2, and there are clear

Acknowledgements

Work in the authors' laboratory is supported by grants to AWP from the Wellcome Trust (project grant nos. 064785 and 069572) and the British Heart Foundation (grant nos. PG/04/097/17620, FS/04/023, FS/05/017). We apologise to those authors whose work we have not cited for space reasons.

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