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SHP‐2 regulates the phosphatidylinositide 3′‐kinase/Akt pathway and suppresses caspase 3‐mediated apoptosis
Author(s) -
Ivins Zito Christina,
Kontaridis Maria I.,
Fornaro Mara,
Feng GengShen,
Bennett Anton M.
Publication year - 2004
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10446
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , microbiology and biotechnology , protein tyrosine phosphatase , pleckstrin homology domain , proto oncogene tyrosine protein kinase src , tyrosine kinase , signal transduction , chemistry , sh2 domain , cancer research , biology
The Src homology domain 2 (SH2)‐containing tyrosine phosphatase SHP‐2 has been implicated in the regulation of the phosphatidylinositol 3′‐kinase (PI3K)/Akt pathway. The ability of SHP‐2 to regulate the PI3K/Akt pathway is suggested to result in the positive effect of SHP‐2 on cell survival. Whether SHP‐2 regulates insulin‐like growth factor‐1 (IGF‐1)‐dependent activation of Akt at the level of PI3K has yet to be established. Furthermore, the identification of the down‐stream apoptotic target engaged by SHP‐2 in cell survival also has yet to be determined. Here, we show that overexpression of a catalytically inactive mutant of SHP‐2 inhibited insulin‐like growth factor‐1 (IGF‐1)‐dependent PI3K and Akt activation. Consistent with the observation that SHP‐2 participates in pro‐survival signaling fibroblasts expressing a deletion within exon 3 of SHP‐2, which results in a truncation of the amino‐terminus SH2 domain (SHP‐2 Ex3−/− ), were hypersensitive to etoposide‐induced cell death. SHP‐2 Ex3−/− fibroblasts exhibited enhanced levels of etoposide‐induced caspase 3 activity as compared to wild‐type fibroblasts and the enhanced level of caspase 3 activity was suppressed by a caspase 3‐specific inhibitor. Re‐introduction of wild‐type SHP‐2 into the SHP‐2 Ex3−/− fibroblasts rescued the hypersensitivity to etoposide‐induced caspase 3 activation. The effects of abrogating SHP‐2 function on cell survival were not specific to the loss of the amino‐terminus SH2 domain of SHP‐2 since RNAi‐mediated knock‐down of SHP‐2 also reduced cell survival. Taken together, these data indicate that the catalytic activity of SHP‐2 is required to regulate the PI3K/Akt pathway and thus likely participates in anti‐apoptotic signaling by suppressing caspase 3‐mediated apoptosis. J. Cell. Physiol. 199: 227–236, 2004© 2003 Wiley‐Liss, Inc.