Abstract
The Src homology 2 domain-containing protein tyrosine phosphatases SHP-1 and SHP-2 play an important role in many intracellular signaling pathways. Both SHP-1 and SHP-2 have been shown to interact with a diverse range of cytosolic and membrane-bound signaling proteins. Generally, SHP-1 and SHP-2 perform opposing roles in signaling processes; SHP-1 acts as a negative regulator of transduction in hemopoietic cells, whereas SHP-2 acts as a positive regulator. Intriguingly, SHP-1 has been proposed to play a positive regulating role in nonhemopoietic cells, although the mechanisms for this are not understood. Here we show that green fluorescent protein-tagged SHP-1 is unexpectedly localized within the nucleus of transfected HEK293 cells. In contrast, the highly related SHP-2 protein is more abundant within the cytoplasm of transfected cells. In accordance with this, endogenous SHP-1 is localized within the nucleus of several other nonhemopoietic cell types, whereas SHP-2 is distributed throughout the cytoplasm. In contrast, SHP-1 is confined to the cytoplasm of hemopoietic cells, with very little nuclear SHP-1 evident. Using chimeric SHP proteins and mutagenesis studies, the nuclear localization signal of SHP-1 was identified within the C-terminal domain of SHP-1 and found to consist of a short cluster of basic amino acids (KRK). Although the KRK motif resembles half of a bipartite nuclear localization signal, it appears to function independently and is absolutely required for nuclear import. Our findings show that SHP-1 and SHP-2 are distinctly localized within nonhemopoietic cells, with the localization of SHP-1 differing dramatically between nonhemopoietic and hemopoietic cell lineages. This implies that SHP-1 nuclear import is a tightly regulated process and indicates that SHP-1 may possess novel nuclear targets.
Highlights
In hemopoietic cells and moderately in many other cell types, especially malignant epithelial cells (4 – 6), whereas SHP-2 is more widely distributed
SHP-1 Is Localized within the Nucleus of HEK293 Cells—A knowledge of the intracellular distribution of nontransmembranal Proteintyrosine phosphatases (PTPs) might give an insight into their cellular function and regulation
It is widely believed that both SHP-1 and SHP-2 are located within the cytoplasm, presumably because their interactions with tyrosine-phosphorylated, membrane-associated proteins are well documented
Summary
The Src homology 2 domain-containing protein tyrosine phosphatases SHP-1 and SHP-2 play an important role in many intracellular signaling pathways. In hemopoietic cells and moderately in many other cell types, especially malignant epithelial cells (4 – 6), whereas SHP-2 is more widely distributed Both proteins are structurally very similar, comprising two tandem Src homology 2 domains at the N terminus, a single central catalytic domain, and a C-terminal domain [7, 8]. SHP-2 plays a positive role in many signaling systems and can act as an adapter protein, linking tyrosine kinases and Grb to activate the mitogen-activated protein kinase pathway [19, 20]. We show that SHP-1 localization differs between nonhemopoietic and hemopoietic cells, with the SHP-1 protein being present almost entirely within the cytoplasm of hemopoietic cell lines. These results have implications regarding the function of SHP-1 in nonhemopoietic cells
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