The Syk tyrosine kinase suppresses malignant growth of human breast cancer cells

Abstract

Syk is a protein tyrosine kinase that is widely expressed in haematopoietic cells. It is involved in coupling activated immunoreceptors to downstream signalling events that mediate diverse cellular responses including proliferation, differentiation and phagocytosis. Syk expression has been reported in cell lines of epithelial origin, but its function in these cells remains unknown. Here we show that Syk is commonly expressed in normal human breast tissue, benign breast lesions and low-tumorigenic breast cancer cell lines. Syk messenger RNA and protein, however, are low or undetectable in invasive breast carcinoma tissue and cell lines. Transfection of wild-type Syk into a Syk-negative breast cancer cell line markedly inhibited its tumour growth and metastasis formation in athymic mice. Conversely, overexpression of a kinase-deficient Syk in a Syk-positive breast cancer cell line significantly increased its tumour incidence and growth. Suppression of tumour growth by the reintroduction of Syk appeared to be the result of aberrant mitosis and cytokinesis. We propose that Syk is a potent modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas.

The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

“…Binding of Syk to the ITAMs of FcRg and DAP12 was shown to regulate the development of osteoclasts (Fodor et al, 2006) and SLP76 and Syk participate in the developmental separation of blood and lymphatic vascular epithelial cells, perhaps dependent on an as yet unidentified ITAM-containing receptor (Koretzky et al, 2006). The observation that Syk acts as a tumor suppressor gene in breast carcinoma (Coopman et al, 2000) has raised the question whether LMP2A might contribute to the tumorigenic development in nasopharyngeal carcinoma through its effects on Syk (Lu et al, 2006). ITAM motifs are present in a number of viral proteins (Grande et al, 2006).…”

The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase

“…Chief among these is the RING-H2-finger domain that could facilitate protein -protein interaction(s) leading to the degradation of specific substrate(s) involved in oncogenesis and the PY motif that could bind to WW domain proteins, including several HECTtype E3 ligases such as NEDD4, AIP4 and Smurf2. The PPPPY motif sequence of RNF11 is identical to that of Smads 2, 3 and 7, which have been shown to bind WW domains of Smurf2 Ub ligase and mediate the ubiquitination and degradation of various target proteins (Coopman et al, 2000;Longnecker et al, 2000). Smurf2 plays a key role in the ubiquitination and proteasomal degradation of receptor-activated Smad2 and Smad3, and corepressor SnoN (Bonni et al, 2001;Mizuide et al, 2003).…”

In-depth Analyses of Kinase-dependent Tyrosine Phosphoproteomes Based on Metal Ion-functionalized Soluble Nanopolymers

“…Among the tumor suppressors identified in breast cancer is Syk, a protein-tyrosine kinase whose expression is reduced in many breast cancer cells and is completely absent in highly tumorigenic cells (19,20). Moreover, when re-expressed in malignant breast cancer cells, Syk inhibits cell motility, growth, invasiveness, and tumor formation while promoting cell-cell adhesion (19). Although the role of Syk in signaling through antigen receptors is well characterized, little is known about the effectors and the pathways that it regulates in breast epithelial cells.…”