Tumor cell migration and invasion are regulated by expression of variant integrin glycoforms

133

Background: Molecular mechanisms of the effect of the GOLPH3 oncogenic protein on tumorigenesis remain unclear. Results: GOLPH3 specifically up-regulates sialylation of integrin N-glycans, promotes sialylation-dependent cell migration, and affects AKT signaling. Conclusion: GOLPH3 affects cell biological functions through a specific regulation of sialylation. Significance: The sialylation of N-glycans is important for functions of GOLPH3.

Section: Discussionsupporting

confidence: 90%

An Oncogenic Protein Golgi Phosphoprotein 3 Up-regulates Cell Migration via Sialylation

Isaji

et al. 2014

133

“…A pooled population of clones stably expressing shRNA was generated by puromycin selection. Down-regulation of ST6Gal-I expression was confirmed by Western blot (19). SW48 cells were purchased from ATCC.…”

Section: Methodsmentioning

confidence: 99%

Sialylation of the Fas Death Receptor by ST6Gal-I Provides Protection against Fas-mediated Apoptosis in Colon Carcinoma Cells

Swindall

Bellis

2011

Self Cite

189

159

The glycosyltransferase, ST6Gal-I, adds sialic acid in an ␣2-6 linkage to the N-glycans of membrane and secreted glycoproteins. Up-regulation of ST6Gal-I occurs in many cancers, including colon carcinoma, and correlates with metastasis and poor prognosis. However, mechanisms by which ST6Gal-I facilitates tumor progression remain poorly understood due to limited knowledge of enzyme substrates. Herein we identify the death receptor, Fas (CD95), as an ST6Gal-I substrate, and show that ␣2-6 sialylation of Fas confers protection against Fas-mediated apoptosis. Intriguingly, differences in ST6Gal-I activity do not affect the function of DR4 or DR5 death receptors upon treatment with TRAIL, implicating a selective effect of ST6Gal-I on the Fas receptor. Using ST6Gal-I knockdown and forced overexpression colon carcinoma cell models, we find that ␣2-6 sialylation of Fas prevents apoptosis stimulated by FasL as well as the Fas-activating antibody, CH11, as evidenced by decreased activation of caspases 8 and 3. We also show that ␣2-6 sialylation of Fas does not alter the binding of CH11, but rather inhibits the capacity of Fas to induce apoptosis by blocking the association of FADD with Fas cytoplasmic tails, an event that initiates death-inducing signaling complex formation. Furthermore, ␣2-6 sialylation of Fas inhibits Fas internalization, which is required for apoptotic signaling. Although dysregulated Fas activity is a well known mechanism through which tumors evade apoptosis, the current study is the first to link Fas insensitivity to the actions of a specific sialyltransferase. This finding establishes a new paradigm by which death receptor function is impaired for the self-protection of tumors against apoptosis.

“…ST6Gal-I is overexpressed in many types of human cancers, including colon (58 -62), breast (63), ovarian (64), gastric (65), oral (66), cervical (67), choriocarcinoma (68), leukemia (69), and brain tumors (70), and high expression positively correlates with tumor metastasis and poor prognosis (61,63,66). Furthermore, both in vitro cell culture and animal studies have implicated ST6Gal-I in regulating tumor cell invasiveness and differentiation state, as well as metastasis (71)(72)(73)(74)(75)(76)(77)(78)(79). Although mechanisms regulating ST6Gal-I expression have not been widely investigated, it is known that ST6Gal-I is up-regulated by oncogenic Ras (reviewed in Ref.…”

Section: St6gal-i-dependent Inhibition Of Galectin Function May Promomentioning

confidence: 99%

Emerging Role of α2,6-Sialic Acid as a Negative Regulator of Galectin Binding and Function

Zhuo

Bellis

2011

Self Cite

155

122

Galectins are ␤-galactoside-binding lectins that regulate diverse cell behaviors, including adhesion, migration, proliferation, and apoptosis. Galectins can be expressed both intracellularly and extracellularly, and extracellular galectins mediate their effects by associating with cell-surface oligosaccharides. Despite intensive current interest in galectins, strikingly few studies have focused on a key enzyme that acts to inhibit galectin signaling, namely ␤-galactoside ␣2,6-sialyltransferase (ST6Gal-I). ST6Gal-I adds an ␣2,6-linked sialic acid to the terminal galactose of N-linked glycans, and this modification blocks galectin binding to ␤-galactosides. This minireview summarizes the evidence suggesting that ST6Gal-I activity serves as an "off switch" for galectin function.Sialic acids comprise a family of nine-carbon sugars added to the termini of oligosaccharides found on secreted or cellsurface glycoproteins and glycolipids (1). Because of their negative charge and relatively large size, sialic acids can mask important functional domains on surface glycoproteins and also serve more generally to protect the cell from various types of assault (2). However, evidence is emerging that sialic acids mediate specific cellular and molecular recognition by regulating association with glycan-binding proteins such as lectins. For example, sialic acids bind specifically to the siglec 2 family of lectins (3), whereas other types of glycan/lectin interactions are conversely inhibited by sialylation. Thus, sialic acids are positioned to play a pivotal role in regulating lectindependent cell/cell and cell/matrix interactions. Sialic acids are added to glycans via ␣2,3-, ␣2,6-, or ␣2,8-linkages, and these linkages are directed by distinct sialyltransferases. ␤-Galactoside ␣2,6-sialyltransferase (ST6Gal-I) is one of the principal enzymes responsible for the addition of ␣2,6-linked sialic acids to the Gal␤1,4GlcNAc disaccharide (4), which is found mainly on N-glycans and, to a lesser extent, on O-glycans. In this minireview, we summarize the evidence suggesting that ST6Gal-I-mediated ␣2,6-sialylation inhibits binding of N-glycans to galectin-type lectins, thereby serving as a negative regulator of galectin-dependent cell responses (of note, ␣2,6-sialic acid/siglec interactions, although of equal biologic importance, will be not be discussed herein due to the availability of other reviews on this topic (3, 5)). GalectinsGalectins are animal lectins that bind ␤-galactosides through their conserved carbohydrate recognition domains (CRDs) (6, 7). At least 15 mammalian galectins have been identified, and these are subdivided into three different groups based on their biochemical structure (Fig. 1). The prototype group (galectin (Gal)-1, -2, -5, -7, -10, -11, -13, -14, and -15) contains one CRD and a short N-terminal sequence. Members of this group typically assemble into noncovalent homodimers. The chimeric group, of which Gal-3 is the only member, contains one CRD and an extended N-terminal domain with a repeated collagen-like seq...