Then, cell growth in the E2-treated cells (top panel) or control cells (bottom panel) was assayed by MTT staining. more than 60% of total 151 breast cancer cases. The inhibition of Shp2 activity by PHPS1 (a Shp2 inhibitor) delayed the development of dimethylbenz(a)anthracene (DMBA)-induced tumors in the rat mammary gland and also blocked tumor formation in MMTV-pyvt transgenic mice. Estradiol (E2) stimulated protein expression and phosphorylation of Shp2, and induced Shp2 binding to ER and IGF-1R around the membrane to facilitate the phosphorylation of Erk and Akt in breast cancer cells MCF7. Shp2 was also involved in several biological effects of the extranuclear ER-initiated pathway in breast cancer cells. Specific inhibitors (phps1, phps4 and NSC87877) or small interference RNAs (siRNA) of Shp2 remarkably suppressed E2-induced gene transcription (Cyclin D1 and trefoil factor 1 (TFF1)), rapid DNA synthesis and late effects on cell growth. These results introduced a new mechanism for Shp2 oncogenic action and shed new light on extranuclear ER-initiated action in breast tumorigenesis by identifying a novel associated protein, Shp2, for extranuclear ER pathway, which might benefit the therapy of breast cancer. Introduction Recently, an increasing number of studies have found that estrogen can exert its action through a extranuclear estrogen receptor (ER) pathway [1], [2], which is usually thought to be required for the estrogen rapid signal, which triggers cytoplasmic kinase cascades to regulate other signals or activate transcriptional factors. The extranuclear ER pathway is usually involved in several crucial cellular functions such as cell proliferation, migration, secretion, and apoptosis [3], [4]. Knowledge on these novel estrogen actions is now significantly broadening our understanding of breast carcinogenesis, particularly regarding metastasis and drug resistance [5], [6]. However, HAE mechanisms underlying rapid extranuclear responses of estrogen signal are not yet fully comprehended [6], [7]. The extranuclear estrogen receptor includes membrane-associated receptors (such as GPR30/GPER1) and cytoplasmic receptor [8]. Because estrogen receptor (ER) has no intrinsic transmembrane domain name and/or kinase domain name, the cytoplasmic ER requires association-proteins to translocate it to the plasma membrane and trigger the cytoplasmic pathway. Mounting evidences now suggest that a pool of intracellular receptors (IGF-1R and EGFR) and membrane receptor adapter proteins (G-protein, Shc, Src, p85, and so on) are associated with the cytoplasmic ER signal pathway [9]C[11]. These associated proteins activate several cytoplasmic cascades, including PLC-PKC [12], [13], Ras-Raf-MAPK [14], [15], Src-PI3K-AKT [16], and cAMP-PKA [17]. Downstream pathways then lead to diversified cell type-specific estrogen actions, such as the triggering of the Ras-Raf-MAPK pathway in epithelial cells [15], Src-AKT-eNOS pathway in endothelial cells [18], or the PLC-cAMP-PKA pathway in neurons and intestinal cells. Therefore, the different expression patterns of these three party proteins are viewed as key factors in response to multiform and cell type-specific estrogen actions. Tyrosine phosphatase protein Shp2 is usually a ubiquitously expressed and multifunctional protein [19], [20]. It consists of two Src homology 2 (SH2) domains and a protein tyrosine phosphatase (PTP) domain name [19], [20]. Shp2 is usually induced to bind with the tyrosine residues of an phosphorylated protein (such as growth factor receptors) by two SH2 domains, and then dephosphorylates this protein activity HAE with PTP domain name [20]. But, the PTP activity of Shp2 is now believed to be required for the activation of several cytoplasmic protein kinases, such as Ras-raf-MAPK, PI3K-AKT and cAMP-PKA [19], [20]. By promoting the activation of these kinase proteins, Shp2 positively regulates cell growth and differentiation, organ development, immunological reaction, as well as metabolism. Shp2 is also involved in numerous diseases [21], [22], especially cancer [23], [24]. The human Shp2 gene, ptpn11, is regarded as the first proto-oncogene in the PTP family [23]. Its activated mutations are found in around 35% of sporadic juvenile myelomonocytic leukemia cases [25], and also in sporadic cases of several solid tumors such as those in the lung [26], [27], colon [28], [29], liver [30], and brain [31]. However, reports on the biological role of Shp2 in solid tumors are not compatible. Shp2 is usually overexpressed in gastric cancer and promotes tumor development PKP4 [32], [33]; But, deletion of Shp2 in liver induces tumor formation in the mouse HAE model [34]. Shp2, in cooperation with GRB2-associated binding protein 2 (Gab2), increases the proliferation of human breast epithelial MCF10A cells and enhances the metastasis of Her2/Neu-induced breast tumors in the transgenic mouse model [35]C[37]. Recently, Shp2 deletion has been found to block the growth and invasion of MCF10A cells in three-dimensional cultures, as well as reduces the.
Then, cell growth in the E2-treated cells (top panel) or control cells (bottom panel) was assayed by MTT staining
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a 67 kDa type I transmembrane glycoprotein present on myeloid progenitors
and differentiation. The protein kinase family is one of the largest families of proteins in eukaryotes
Apoptosis
bladder
brain
breast
cell cycle progression
cervix
CSP-B
Cyproterone acetate
EGFR) is the prototype member of the type 1 receptor tyrosine kinases. EGFR overexpression in tumors indicates poor prognosis and is observed in tumors of the head and neck
EM9
endometrium
erythrocytes
F3
Goat polyclonal to IgG H+L)
Goat polyclonal to IgG H+L)Biotin)
GRK4
GSK1904529A
Igf1
Mapkap1
monocytes andgranulocytes. CD33 is absent on lymphocytes
Mouse monoclonal to CD33.CT65 reacts with CD33 andtigen
Palomid 529
platelets
PTK) or serine/threonine
Rabbit Polyclonal to ARNT.
Rabbit polyclonal to BMPR2
Rabbit Polyclonal to CCBP2.
Rabbit Polyclonal to EDG4
Rabbit polyclonal to EIF4E.
Rabbit polyclonal to IL11RA
Rabbit polyclonal to LRRIQ3
Rabbit Polyclonal to MCM3 phospho-Thr722)
Rabbit Polyclonal to RBM34
SB 216763
SKI-606
SNX-5422
STK) kinase catalytic domains. Epidermal Growth factor receptor
stomach
stomach and in squamous cell carcinoma.
TNFSF8
TSHR
VEGFA
vulva