The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury

Abstract

Interest in the diverse biology of protein tyrosine phosphatases that are encoded by more than 100 genes in the human genome continues to grow at an accelerated pace. In particular, two cytoplasmic protein tyrosine phosphatases composed of two Src homology 2 (SH2) NH2-terminal domains and a C-terminal protein-tyrosine phosphatase domain referred to as SHP-1 and SHP-2 are known to govern a host of cellular functions. SHP-1 and SHP-2 modulate progenitor cell development, cellular growth, tissue inflammation, and cellular chemotaxis, but more recently the role of SHP-1 and SHP-2 to directly control cell survival involving oxidative stress pathways has come to light. SHP-1 and SHP-2 are fundamental for the function of several growth factor and metabolic pathways yielding far reaching implications for disease pathways and disorders such as diabetes, neurodegeneration, and cancer. Although SHP-1 and SHP-2 can employ similar or parallel cellular pathways, these proteins also clearly exert opposing effects upon downstream cellular cascades that affect early and late apoptotic programs. SHP-1 and SHP-2 modulate cellular signals that involve phosphatidylinositol 3-kinase, Akt, Janus kinase 2, signal transducer and activator of transcription proteins, mitogen-activating protein kinases, extracellular signal-related kinases, c-Jun-amino terminal kinases, and nuclear factor-kappaB. Our progressive understanding of the impact of SHP-1 and SHP-2 upon multiple cellular environments and organ systems should continue to facilitate the targeted development of treatments for a variety of disease entities.

Fig. 1

Oxidative stress leads to significant externalization of phosphatidylserine (PS) residues in SHP-2 mutant neurons. Murine neurons lacking SHP-2 function were labeled with annexin V phycoerythrin 5 hours following exposure to oxidative stress with a nitric oxide (NO) agent (NOC-9, 300 mM). Imaging uses transmitted light, corresponding fluorescence light, and superimposed transmitted and fluorescent images of the same microscopy field at 490 nm excitation and 585 nm emission wavelengths to locate the annexin V phycoerythrin label (red-green).

Fig. 2

Absence of SHP-2 function in neurons leads to increased phosphatidylserine (PS) exposure and DNA fragmentation during oxidative stress. (A) Wildtype murine neurons or neurons lacking SHP-2 function were labeled with annexin V phycoerythrin 3, 12, and 24 hours following exposure to oxidative stress with a nitric oxide (NO) agent (NOC-9, 300 mM) and the percentage of membrane PS exposure was determined at each time point. The percentage of PS exposure progressively increased to a greater extent in neurons lacking SHP-2 cells over a 24 hour period, suggesting a protective role for SHP-2 against apoptotic early PS externalization (*p<0.01 versus untreated control; *p<0.01 versus corresponding concentration of NO treated wildtype neurons). Each data point represents the mean and SEM. (B) Increasing concentrations of NO donor (NOC-9, 50–300 mM) to lead to oxidative stress was applied to wildtype murine neurons or neurons lacking SHP-2 function and DNA fragmentation was determined 24 hours later using the terminal deoxynucleotidyl transferase nick end labeling assay. Exposure to NO resulted in a greater increase in DNA fragmentation in neurons lacking SHP-2, suggesting a protective role for SHP-2 against apoptotic DNA injury (*p<0.01 versus untreated control; †p<0.01 versus corresponding concentration of NO treated wildtype neurons). Each data point represents the mean and SEM.

Fig. 3

Illustration of potential signaling pathways controlled by Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1). SHP-1 plays an important role in the regulation of growth factor and cytokine signal transduction to modulate cell proliferation, differentiation, survival, and apoptosis. SHP-1 can regulate growth factor induced activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt and nuclear factor-kappa B (NF-κB). SHP-1 may either negatively or positively regulate the activation of the extracellular signal-related kinases (ERKs) and the c-Jun-amino terminal kinases (JNKs). In addition, SHP-1 can bind to the erythropoietin (EPO) receptor via its SH2 domain and modulate EPO activation of the Janus kinase 2 (Jak2)/signal transducer and activator of transcription (STAT).

Fig. 4

Illustration of potential signaling pathways controlled by Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP-2). Similar to SHP-1, SHP-2 has a critical role in a host of cellular signal transduction pathways that involve cell proliferation, differentiation, survival, and apoptosis. Through the association with Grb2-associated binder-1 (Gab1), a docking protein containing an N-terminal pleckstrin homology domain and several proline-rich SH3 domain-binding sequences, SHP-2 promotes growth factor induced activation of phosphatidylinositol 3-kinase (PI 3-K)/Akt, the extracellular signal-related kinases (ERKs), and nuclear factor-kappa B (NF-κB). SHP-2 can either negatively or positively regulate the activation of Janus kinase 2 (Jak2)/signal transducer and activator of transcription (STAT) and the c-Jun-amino terminal kinases (JNKs) depending on different circumstances.