SHP-1 and SHP-2 are two
Src homology 2 domain-containing tyrosine phosphatases with major
pathological implications in
cell growth regulating signaling. They share significant overall
sequence identity, but their biological functions are often opposite. SHP-1 is generally considered as a negative
signal transducer and SHP-2 as a positive one. However, the precise role of each
enzyme in shared
signaling pathways is not well defined. In this study, we investigated the interaction of these two
enzymes in a single cell system by knocking down their expressions with small interfering
RNAs and analyzing the effects on
epidermal growth factor signaling. Interestingly,
knockdown of either SHP-1 or SHP-2 caused
significant reduction in the
activation of
ERK1/2 but not
Akt. 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 because it was abrogated by
knockdown of SHP-2, and SHP-2, but not SHP-1, binds directly to tyrosine-phosphorylated Gab1. Together, the data revealed that both SHP-1 and SHP-2 have a positive role in epidermal growth factor-induced
ERK1/2
activation and that they act cooperatively rather than antagonistically. The interaction of SHP-1 and SHP-2 may be responsible for previously unexpected novel regulatory mechanism of
cell signaling by
tyrosine phosphatases.
