Recovery of anoikis in Src-transformed cells and human breast carcinoma cells by restoration of the SIRP α1/SHP-2 signaling system.

Src kinase dysregulation contributes to cancer progression but mechanistic understanding for this contribution remains incomplete. Signal regulatory protein α1 (SIRPα1) is a tumor suppressor that is constitutively suppressed in v-Src-transformed cells, where restoration of SIRPα1 expression inhibits anchorage-independent growth. In this study, we investigated the role of the protein tyrosine phosphatase-2 (SHP-2) in SIRPα1 activity. SHP-2 suppression resulted in a blockade of SIRPα1-mediated inhibition of anchorage-independent growth. Notably, we found that SIRPα1 did not act in v-Src-transformed cells by triggering cell growth arrest but by eliciting a suspension-selective apoptosis (anoikis), and that SHP-2 was required for this effect. Furthermore, we found that SHP-2 was crucial for recovery of stress fiber and focal contact formation by SIRPα1 in v-Src-transformed cells. Finally, we found that SIRPα1/SHP-2 signaling regulates anoikis in human breast carcinoma cells with activated c-Src. Taken together, our findings define SHP-2 as an essential component of tumor suppression and anoikis mediated by SIRPα1 in human breast carcinoma cells as well as in v-Src-transformed cells.

Hara K ，Senga T ，Biswas MH ，Hasegawa H ，Ito S ，Hyodo T ，Hirooka Y ，Niwa Y ，Goto H ，Hamaguchi M ... -  《-》

Transcriptional regulation of signal regulatory protein alpha1 inhibitory receptors by epidermal growth factor receptor signaling.

Kapoor GS ，Kapitonov D ，O'Rourke DM 《CANCER RESEARCH》

Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by signal-regulatory proteins (SIRPs).

Wu CJ ，Chen Z ，Ullrich A ，Greene MI ，O'Rourke DM ... -  《ONCOGENE》

Negative regulation of hepatocellular carcinoma cell growth by signal regulatory protein alpha1.

Signal regulatory protein (SIRP) alpha1 is a member of the SIRP family that undergoes tyrosine phosphorylation and binds SHP-2 tyrosine phosphatase in response to various mitogens. The expression levels of SIRPalpha1 were decreased in HCC tissues, compared with the matched normal tissues. Exogenous expression of wild type SIRPalpha1, but not of a mutant SIRPalpha1 lacking the tyrosine phosphorylation sites, in SIRPalpha1-negative Huh7 human HCC cells resulted in suppression of tumor cell growth both in vitro and in vivo. Treatment of Huh7 transfectants with EGF or HGF induced tyrosine phosphorylation of SIRPalpha1 and its association with SHP-2, which were accompanied by reduced ERK1 activation. Expression of SIRPalpha1 significantly suppressed activation of NF-kappaB and also sensitized Huh7 cells to TNFalpha or cisplatin-induced cell death. In addition, SIRPalpha1-transfected Huh7 cells displayed reduced cell migration and cell spreading in a fashion that was dependent on SIRPalpha1/SHP-2 complex formation. In conclusion, a negative regulatory effect of SIRPalpha1 on hepatocarcinogenesis is exerted, at least in part, through inhibition of ERK and NF-kappaB pathways.

Yan HX ，Wang HY ，Zhang R ，Chen L ，Li BA ，Liu SQ ，Cao HF ，Qiu XH ，Shan YF ，Yan ZH ，Wu HP ，Tan YX ，Wu MC ... -  《HEPATOLOGY》

SIRPalpha1 and SIRPalpha2: their role as tumor suppressors in breast carcinoma cells.

Yamasaki Y ，Ito S ，Tsunoda N ，Kokuryo T ，Hara K ，Senga T ，Kannagi R ，Yamamoto T ，Oda K ，Nagino M ，Nimura Y ，Hamaguchi M ... -  《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》