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Coordinated regulation of epidermal Growth Factor Signaling by the protein tyrosine phosphatases SHP‐1 and SHP‐2
Author(s) -
Wang Ning,
Ding Ronghua,
Frank Gerald D.,
Senbonmatsu Takaaki,
Landon Erwin J,
Inagami Tadashi
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a923-d
Subject(s) - protein tyrosine phosphatase , gene knockdown , epidermal growth factor , microbiology and biotechnology , phosphatase , mapk/erk pathway , signal transduction , phosphorylation , proto oncogene tyrosine protein kinase src , chemistry , biology , cancer research , biochemistry , receptor , apoptosis
SHP‐1 and SHP‐2 are two SH2 domain‐containing tyrosine phosphatases. They share significant overall sequence identity, but their biological functions are often opposite. SHP‐1 is generally considered as a negative signal transducer while SHP‐2 as a positive one. However, the precise role of each enzyme in shared signaling pathways is not well defined. Methods We examined roles of SHP‐1 and SHP‐2 on epidermal growth factor signaling in Coca‐2 cell line expressing both phosphatases by knocking down these enzymes with specificity siRNAs. Result Knockdown of either SHP‐1 or SHP‐2 caused significant reduction in the activation of ERK1/2. However, knockdown of both enzymes simultaneously diminished such an effect, suggesting that SHP‐1 and SHP‐2 rely on each other to up‐regulate the ERK1/2 activation. Furthermore, SHP‐1, SHP‐2, and Gab1 formed a signaling complex, and SHP‐1 and SHP‐2 interact with each other. The interaction of SHP‐1 with Gab1 is mediated by SHP‐2 since it was abrogated by knockdown of SHP‐2. Conclusion The data revealed that both SHP‐1 and SHP‐2 have a positive role in epidermal growth factor‐induced ERK activation and that they act cooperatively rather than antagonistically This work was supported by grant HL058205 (to T. Inagami) from the National Institutes of Health.