SHP-2, SH2-containing protein tyrosine phosphatase-2

doi:10.1016/S1357-2725(98)00002-8

The International Journal of Biochemistry & Cell Biology

Volume 30, Issue 5, 1 May 1998, Pages 559-566

https://doi.org/10.1016/S1357-2725(98)00002-8 Get rights and content

Abstract

SHP-2 is an ubiquitously expressed cytosolic protein tyrosine phosphatase composed of two amino-terminal SH2 domains, a central phosphatase domain and a carboxy-terminal tail. Upon activation of cells with different stimuli, SHP-2 is recruited to the plasma membrane where it can associate with a number of tyrosine phosphorylated molecules, including receptor tyrosine kinases (e.g. growth factor receptors), multisite adapter proteins and cell adhesion molecules. SHP-2 is thought to function as a positive mediator of signals generated by activated membrane receptor complexes although the number and diversity of binding partners and substrates identified thus far suggests that it may have other functions. It is likely that several negative regulatory influences exist but that these are obscured by its positive function making the investigation of the inhibitory effects of this phosphatase difficult. The positive regulatory role of SHP-2 in signal cascades leading to cell growth suggests involvement in tumorigenesis, raising the possibility that SHP-2 may be a target in the treatment of some forms of cancer.

Introduction

The generation of physiological signals that regulate fundamental biological processes such as cell growth, differentiation, survival and the maintenance of metabolic homeostasis involve the reversible phosphorylation of proteins on tyrosine residues. In this process, autophosphorylation of receptor-type tyrosine kinases, upon activation by polypeptide ligands, creates binding sites for signal transfer molecules containing src homology 2 (SH2) domains. The level of tyrosine phosphorylation of cellular proteins is determined by the balance between the actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). A key issue in understanding the control of signal transduction is how these two types of enzymes, with opposing catalytic functions, are coordinately regulated.

SHP-2, also known as PTP1D, SHPTP-2, SHPTP-3, PTP2C or Syp, is an ubiquitously expressed cytosolic protein tyrosine phosphatase (PTP) containing two src homology 2 (SH2) domains that was cloned in 1993 by different laboratories. At that time it was the third member of this subfamily of non-receptor PTPs. The first representative, SHP-1 (PTP1C, SHPTP-1, HCP), cloned in 1991, is expressed predominantly in hematopoietic cell types although its expression has also been observed in epithelial cells, including breast cancer cell lines. In 1992 the Drosophila corkscrew (csw) gene product was identified as the second member of this subfamily. Sequence homology, expression pattern and the biological function suggest that Corkscrew is the Drosophila SHP-2 homologue.

Section snippets

Structure and function

The protein tyrosine phosphatase SHP-2 is composed of two src homology 2 (SH2) domains at the amino-terminus, a single central phosphatase domain and a carboxy-terminal tail (Fig. 1). At least two tyrosine phosphorylation sites were identified suggesting that SHP-2 can interact with other SH2 domain containing molecules.

Deletion of the SH2 domains of SHP-2 or their association with tyrosine phosphorylated peptides, leads to an activation of the phosphatase suggesting that the SH2 domains

Expression and variants

The human gene encoding SHP-2 was located to the chromosomal region 12q24.1[6]. Transcription leads to a single, approximately 7 kb mRNA product that was found in almost all tissues and cell lines investigated so far. Northern blot analysis revealed that SHP-2 is abundant in brain, heart and skeletal muscle. During mouse development, SHP-2 mRNA was detected in early stages (day 7.5) in embryonic, extraembryonic and maternal tissues. In situ hybridization revealed only small variations in the

Biological function

Upon activation of cells with different stimuli SHP-2 is targeted to specific tyrosyl phosphorylated proteins via its tandem SH2 domains. These molecules include receptor tyrosine kinases such as platelet-derived growth factor receptor (PDGF-R), insulin receptor (IR), insulin-like growth factor receptor 1 (IGF1-R), epidermal growth factor receptor (EGF-R), cytokine receptors including erythropoietin receptor (EPO-R) and gp130, adapter proteins with pleckstrin homology (PH) domains such as

Role in disease processes

Despite the positive function of SHP-2 in diverse signal transduction pathways, no mutation has been identified that renders the protein oncogenic. Interestingly, when Csw was artificially inserted into the membrane the sevenless pathway was shown to be activated[1]. Comparable experiments in mammalian cells remain to be done to examine whether the translocation of SHP-2 to the membrane alone is sufficient to constitutively activate MAPK or to transform cells.

The specific inactivation of SHP-2

Acknowledgements

We thank Oliver Nayler for critical comments on the manuscript. This work was supported by a grant from SUGEN, Inc.

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¹: Due to the limitation of references we would like to apologize to all authors that contributed important results to the elucidation of the biological function of SHP-2 and could not be mentioned in this review.

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Molecules in focusSHP-2, SH2-containing protein tyrosine phosphatase-21

Abstract

Introduction

Section snippets

Structure and function

Expression and variants

Biological function

Role in disease processes

Acknowledgements

Trends Genet.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Molecules in focus
SHP-2, SH2-containing protein tyrosine phosphatase-2¹