The Src-homology domain 2 (SH2)-containing cytoplasmic tyrosine phosphatase
, SHP-1 (SH2-containing protein tyrosine phosphatase-1), interacts with sev
eral B cell surface and intracellular signal transduction molecules through
its SH2 domains. Mice with the motheaten and viable motheaten mutations ar
e deficient in SHP-1 and lack most mature B cells. To define the role of SH
P-1 in mature B cells, we expressed phosphatase-inactive SHP-1 (C453S) in a
mature B cell lymphoma line. SHP-1 (C453S) retains the ability to bind to
both substrates and appropriate tyrosine-phosphorylated proteins and theref
ore can compete with the endogenous wild-type enzyme. We found that B cells
expressing SHP-1 (C453S) demonstrated enhanced and prolonged tyrosine phos
phorylation of proteins with molecular masses of 110, 70, and 55-60 kDa aft
er stimulation with anti-mouse IgG, The tyrosine kinase Syk was hyperphosph
orylated and hyperactive in B cells expressing SHP-1 (C453S), SHP-1 and Syk
were coimmunoprecipitated from wild-type K46 cells, K46 SHP-1 (C453S) cell
s, and splenic B cells, and SHP-1 dephosphorylated Syk. Cells expressing SH
P-1 (C453S) showed increased Ca2+ mobilization, extracellular signal-regula
ted kinase activation, and homotypic adhesion after B cell Ag receptor enga
gement. Thus, SHP-1 regulates multiple early and late events in B lymphocyt
e activation.