Immunol Rev. 2009 Mar;228(1):342-59.

SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels.

Source

Department of Microbiology and The Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908-0734, USA. ulorenz@virginia.edu

Abstract

Tyrosine phosphorylation and dephosphorylation of proteins play a critical role for many T-cell functions. The opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) determine the level of tyrosine phosphorylation at any time. It is well accepted that PTKs are essential during T-cell signaling; however, the role and importance of PTPs are much less known and appreciated. Both transmembrane and cytoplasmic tyrosine phosphatases have been identified in T cells and shown to regulate T-cell responses. This review focuses on the roles of the two cytoplasmic PTPs, the Src-homology 2 domain (SH2)-containing SHP-1 and SHP-2, in T-cell signaling, development, differentiation, and function.

PMID:: 19290938; [PubMed - indexed for MEDLINE]
PMCID:: PMC2669678

Free PMC Article

Images from this publication.See all images (2) Free text

Fig. 2

Two alternative models depicting thymic development of natural CD4⁺CD25⁺Foxp3⁺ Treg cells

In the model of increased selection (model 1), thymocytes undergoing the selection process at the DP stage are ‘undecided’ and can develop into Treg or conventional non-Treg cells depending on the strength of signal they encounter. CD4+CD25+ Treg cells are selected in response to a defined range of TCR signaling strength that falls between positive selection of non-Treg cells and negative selection/deletion (left panel). Under conditions of increased TCR signaling strength (right panel), such as exposure of the TCR to a high affinity ligand or loss of the negative regulator SHP-1, the selection process shifts towards positive selection of CD4+CD25+ Treg cells and greater deletion of non-Treg cells, resulting in an increase in the absolute number of CD4+CD25+ T cells. In contrast, in the model of pre-commitment/selection (model 2), a defined fraction of the CD4+CD8+ DP thymocytes is already committed to the CD4+CD25+ Treg cell lineage. Whether the pre-commitment is driven by encounter with a signal or by a stochastic process is unknown at this time. The remaining non-committed DP cells have the potential to develop into conventional non-Treg T cells upon passing of positive/negative selection, but lost the potential to develop into Treg cells. The cells pre-committed to the Treg lineage still require additional signals and might undergo a selection process similar to conventional T cell to acquire the Treg phenotype but their absolute numbers are unaffected by the TCR signal strength as long as it is above a certain threshold. Moreover, even when exposed to strong TCR-mediated signaling, these developing CD4+CD25+ Treg cells are highly resistant to deletion. Therefore under conditions of strong TCR signaling strength (right panel), the observed gain in the percentage of CD4+CD25+ Treg cells is due to increased negative selection and selective loss of the CD4+CD25- conventional T cell population.

SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels

Immunol Rev. Immunol Rev;228(1):342-359.

Publication Types, MeSH Terms, Substances, Grant Support

Publication Types

MeSH Terms

Substances

Grant Support

LinkOut - more resources

Full Text Sources

Other Literature Sources

Supplemental Content

Save items

Related citations in PubMed

Targeting Src homology 2 domain-containing tyrosine phosphatase (SHP-1) into lipid rafts inhibits CD3-induced T cell activation. [J Immunol. 2001]
Targeting Src homology 2 domain-containing tyrosine phosphatase (SHP-1) into lipid rafts inhibits CD3-induced T cell activation.
Su MW, Yu CL, Burakoff SJ, Jin YJ. J Immunol. 2001 Mar 15; 166(6):3975-82.
Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells. [Proc Natl Acad Sci U S A. 1998]
Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells.
Migone TS, Cacalano NA, Taylor N, Yi T, Waldmann TA, Johnston JA. Proc Natl Acad Sci U S A. 1998 Mar 31; 95(7):3845-50.
Src homology 2 domain-containing protein-tyrosine phosphatases, SHP-1 and SHP-2, are required for platelet endothelial cell adhesion molecule-1/CD31-mediated inhibitory signaling. [J Immunol. 2001]
Src homology 2 domain-containing protein-tyrosine phosphatases, SHP-1 and SHP-2, are required for platelet endothelial cell adhesion molecule-1/CD31-mediated inhibitory signaling.
Henshall TL, Jones KL, Wilkinson R, Jackson DE. J Immunol. 2001 Mar 1; 166(5):3098-106.
Review Regulation of B cell signal transduction by SH2-containing protein-tyrosine phosphatases. [Semin Immunol. 1998]
Review Regulation of B cell signal transduction by SH2-containing protein-tyrosine phosphatases.
Siminovitch KA, Neel BG. Semin Immunol. 1998 Aug; 10(4):329-47.
Review A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. [Cell Signal. 2005]
Review A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail.
Poole AW, Jones ML. Cell Signal. 2005 Nov; 17(11):1323-32.

See reviews... See all...

Cited by 12 PubMed Central articles

Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects. [Oncotarget. 2011]
Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects.
Yi T, Elson P, Mitsuhashi M, Jacobs B, Hollovary E, Budd TG, Spiro T, Triozzi P, Borden EC. Oncotarget. 2011 Dec; 2(12):1155-64.
The SHP-1 protein tyrosine phosphatase negatively modulates Akt signaling in the ghrelin/GHSR1a system. [Mol Biol Cell. 2011]
The SHP-1 protein tyrosine phosphatase negatively modulates Akt signaling in the ghrelin/GHSR1a system.
Lodeiro M, Alén BO, Mosteiro CS, Beiroa D, Nogueiras R, Theodoropoulou M, Pardo M, Gallego R, Pazos Y, Casanueva FF, et al. Mol Biol Cell. 2011 Nov; 22(21):4182-91. Epub 2011 Sep 7.
Lymphocyte cell-cycle inhibition by HLA-G is mediated by phosphatase SHP-2 and acts on the mTOR pathway. [PLoS One. 2011]
Lymphocyte cell-cycle inhibition by HLA-G is mediated by phosphatase SHP-2 and acts on the mTOR pathway.
Ketroussi F, Giuliani M, Bahri R, Azzarone B, Charpentier B, Durrbach A. PLoS One. 2011; 6(8):e22776. Epub 2011 Aug 24.

See all...

Related information

Related Citations
Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.
OMIM (calculated)
Online Mendelian Inheritance in Man (OMIM) records that include the current articles as references in the light bulb links within or in the citations at the end of the OMIM record. The references available through the light bulb link are collected using the PubMed related articles algorithm to identify records with similar terminology to the OMIM record.
References for this PMC Article
Citation referenced in PubMed article. Only valid for PubMed citations that are also in PMC.
Free in PMC
Free full text articles in PMC
Cited in PMC
Full-text articles in the PubMed Central Database that cite the current articles.

Recent activity

Clear Turn Off Turn On

SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels.
SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels.
Immunol Rev. 2009 Mar ;228(1):342-59.

PubMed
The changing face of phase 1 cancer clinical trials: new challenges in study req...
The changing face of phase 1 cancer clinical trials: new challenges in study requirements.
Cancer. 2009 Apr 15 ;115(8):1592-7.

PubMed
[Mineral metabolism and aluminum burden with hydrotalcit. A placebo-controlled r...
[Mineral metabolism and aluminum burden with hydrotalcit. A placebo-controlled randomized double-blind study].
Fortschr Med. 1991 Jun 20 ;109(18):385-8.

PubMed
Primary care consultations about medically unexplained symptoms: how do patients...
Primary care consultations about medically unexplained symptoms: how do patients indicate what they want?
J Gen Intern Med. 2009 Apr ;24(4):450-6. Epub 2009 Jan 23 .

PubMed
Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis ...
Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.
Eur Arch Psychiatry Clin Neurosci. 2009 Apr ;259(3):151-63. Epub 2009 Jan 22 .

PubMed

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

PubMed

Result Filters

Display Settings:

Send to: