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SHP-1 Phosphatase C-Terminus Interacts With Novel Substrates
p32/p30 During Erythropoietin and Interleukin-3 Mitogenic Responses
Wentian Yang,
Mina Tabrizi,
Karim Berrada, and
Taolin Yi
From the Department of Cancer Biology, The Lerner Research Institute
of the Cleveland Clinic Foundation, Cleveland, OH.
SHP-1 protein tyrosine phosphatase is a critical negative regulator
of mitogenic signaling, as demonstrated by the heightened growth
responses to hematopoietic growth factors in hematopoietic cells of
motheaten mice, which lack functional SHP-1 expression due to mutations
in the SHP-1 gene. The mitogenic signaling molecules dephosphorylated
by SHP-1 have not been fully identified. We detected two proteins
(p32/p30) that are hyperphosphorylated in a DA3/erythropoietin receptor
(EpoR) cell line that expresses a mutant containing the SHP-1
C-terminus that suppresses the function of the endogenous phosphatase
and induces hyperproliferative responses to interleukin-3 (IL-3) and
Epo. Hyperphosphorylated p32/p30 are also detected in motheaten
hematopoietic cells, demonstrating an association of p32/p30
hyperphosphorylation with SHP-1-deficiency and growth factor-hyperresponsiveness. The hyperphosphorylated p32/30 associate with SHP-1 via its C-terminus, because they coimmunoprecipitate with
the phosphatase and the C-terminal mutant and they bind in vitro to a
synthetic peptide of the mutant but not the GST fusion proteins of
SHP-1 SH2 domains. Induction of p32/p30 phosphorylation by IL-3 or Epo
occurs mainly at 2 to 18 hours poststimulation in the DA3/EpoR cell
line, indicating p32/p30 as novel signaling molecules during cell cycle
progression. These data demonstrate a function for the SHP-1 C-terminus
in recruiting potential substrates p32/p30 and suggest that SHP-1 may
regulates mitogenic signaling by dephosphorylating p32/p30.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3746-3755
© 1998 by The American Society of Hematology.
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