Syk Interacts with and Phosphorylates Nucleolin To Stabilize Bcl-x_L mRNA and Promote Cell Survival

Abstract

The Syk protein tyrosine kinase, a well-characterized regulator of immune cell function, plays an increasingly recognized role in tumorigenesis as a promoter of cell survival in both hematological and nonhematological malignancies. We show here that the expression of Syk in MCF7 or MDA-MB-231 breast cancer cells or in DG75 B-lymphoma cells protects cells from apoptosis induced by oxidative or genotoxic stress by stabilizing the mRNA for Bcl-x L , an antiapoptotic protein. Syk binds robustly to nucleolin and phosphorylates it on tyrosine, enhancing its ability to bind the Bcl-x L mRNA. Consequently, reducing the level of nucleolin by RNA interference attenuates the ability of Syk to protect cells from stress-induced cell death.

Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy

“…In many tumors, the expression of Syk enhances cell survival, especially in the face of external or internal factors, including oxidative stress, exposure to chemotherapeutic agents, expression of oncogenes like activated K-Ras, or loss of Rb (4,5,8,9). Multiple mechanisms have been described to account for many of the protective effects of Syk on cells, including activation of the PI3K/Akt pro-survival pathway leading to the stabilization of the anti-apoptotic proteins Mcl-1 and/or XIAP, activation of mTOR, activation of STAT3 or STAT5, enhanced transcription of NF-B-regulated genes, and stabilization of the mRNA for Bcl-xL through an association of Syk with nucleolin (8, 9, 50 -56).…”

“…DNA Constructs and Cell Lines-Lentiviral vectors for the expression of enhanced green fluorescent protein (EGFP)-tagged Syk (Syk-EGFP) and various mutant forms of Syk-EGFP (Syk-EGFP(K396R), Syk-EGFP(Y342F), Syk-EGFP(Y346F), and Syk-EGFP(Y342F/Y346F)) were described previously (9). The cDNA for Syk-EGFP(R428Q/M429L/M442A) (Syk-AQL-EGFP) was amplified by PCR from the corresponding EGFP-N2 (Clontech) construct (32) and cloned into the Tet-inducible lentiviral vector pLVX-Tight-Puro (Clontech).…”

“…The inhibition of or knockdown in expression of Syk promotes apoptosis in multiple cancer cell types, including many hematopoietic malignancies as well as K-Ras-dependent lung and pancreatic cancer (5), small cell lung cancer (6), ovarian cancer (7), and retinoblastoma (8). For many cancer cells, the expression of Syk can protect them from cell death due to genotoxic or oxidative stress (9).…”

Inhibition of Spleen Tyrosine Kinase Potentiates Paclitaxel-Induced Cytotoxicity in Ovarian Cancer Cells by Stabilizing Microtubules

“…SYK has been reported as a candidate oncogene in B-cell leukemia and lymphomas, gastric carcinoma, and head and neck cancer (Buchner et al, 2009; Feldman et al, 2008; Luangdilok et al, 2007; Mocsai et al, 2010; Nakashima et al, 2006). SYK expression has an anti-apoptotic effect on B-lymphoma cell lines through phosphorylation of nucleolin which stabilizes the mRNA of antiapoptotic Bcl-x(L) (Wang et al, 2014). Paradoxically, SYK expression may block tumor progression in breast cancer as loss of its expression is associated with poor prognosis and tumor metastasis (Coopman et al, 2000).…”

Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer

“…In multiple cell types including DLBCL, Burkitt’s lymphoma, and breast carcinoma, an interaction of SYK with nucleolin (NCL) promotes the binding to NCL of the mRNA coding for the anti-apoptotic protein, BCL-XL, but not the alternatively spliced message coding for the smaller pro-apoptotic protein, BCL-XS [92]. This interaction with NCL stabilizes the BCL-XL transcript from being degraded in response to oxidative or genotoxic stress.…”