A Possible Modulation Mechanism of Intramolecular and Intermolecular Interactions for NCAM Polysialylation and Cell Migration

Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression or NCAM polysialylation is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. It has been known that two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST), can catalyze polysialylation of NCAM, and two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs play key roles in affecting polyST activity or NCAM polysialylation. However, the molecular mechanisms of NCAM polysialylation and cell migration are still not entirely clear. In this minireview, the recent research results about the intermolecular interactions between the PBR and NCAM, the PSTD and cytidine monophosphate-sialic acid (CMP-Sia), the PSTD and polySia, and as well as the intramolecular interaction between the PBR and the PSTD within the polyST, are summarized. Based on these cooperative interactions, we have built a novel model of NCAM polysialylation and cell migration mechanisms, which may be helpful to design and develop new polysialyltransferase inhibitors.

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Abstract 4410: Inhibition of cell surface polysialic acid biosynthesis modulates tumor cell migration.

10.1158/1538-7445.am2013-4410 ◽

2013 ◽

Author(s):

Bradley R. Springett ◽

Yousef M.J. Al-Saraireh ◽

Virginie Viprey ◽

Mark Sutherland ◽

Melanie Begouin ◽

...

Keyword(s):

Cell Migration ◽

Cell Surface ◽

Tumor Cell ◽

Polysialic Acid ◽

Acid Biosynthesis ◽

Tumor Cell Migration

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KASH-domain proteins and the cytoskeletal landscapes of the nuclear envelope

Biochemical Society Transactions ◽

10.1042/bst0361368 ◽

2008 ◽

Vol 36 (6) ◽

pp. 1368-1372 ◽

Cited By ~ 10

Author(s):

Maria Schneider ◽

Angelika A. Noegel ◽

Iakowos Karakesisoglou

Keyword(s):

Nuclear Envelope ◽

Nuclear Membrane ◽

Mammalian Cells ◽

Molecular Mechanisms ◽

Nuclear Architecture ◽

Membrane Interface ◽

Novel Proteins ◽

Evolutionarily Conserved ◽

Membrane Tethering ◽

Novel Model

Over the last few years, several novel proteins have been identified that facilitate the physical integration of the nucleus with the cytoplasmic compartment. The majority belong to the evolutionarily conserved KASH [klarsicht/ANC-1 (anchorage 1)/SYNE (synaptic nuclear envelope protein) homology]-domain family, which function primarily as exclusive outer nuclear membrane scaffolds that associate with the cytoskeleton, the centrosome and the motor protein apparatus. In the present paper, we propose a novel model, which may explain why these proteins also determine nuclear architecture. Moreover, we discuss further nuclear membrane-tethering devices, which indicate collectively the presence of specific molecular mechanisms that organize the cytoplasmic–nuclear membrane interface in mammalian cells.

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Functional N-methyl-D-aspartate receptors in O-2A glial precursor cells: a critical role in regulating polysialic acid-neural cell adhesion molecule expression and cell migration.

The Journal of Cell Biology ◽

10.1083/jcb.135.6.1565 ◽

1996 ◽

Vol 135 (6) ◽

pp. 1565-1581 ◽

Cited By ~ 124

Author(s):

C Wang ◽

W F Pralong ◽

M F Schulz ◽

G Rougon ◽

J M Aubry ◽

...

Keyword(s):

Cell Migration ◽

Cell Adhesion ◽

Nmda Receptor ◽

Adhesion Molecule ◽

Cell Adhesion Molecule ◽

Neural Cell Adhesion Molecule ◽

Polysialic Acid ◽

Neural Cell ◽

Adhesion Molecule Expression ◽

Neural Cell Adhesion

The capacity for long-distance migration of the oligodendrocyte precursor cell, oligodendrocyte-type 2 astrocyte (O-2A), is essential for myelin formation. To study the molecular mechanisms that control this process, we used an in vitro migration assay that uses neurohypophysial explants. We provide evidence that O-2A cells in these preparations express functional N-methyl-D-aspartate (NMDA) receptors, most likely as homomeric complexes of the NR1 subunit. We show that NMDA evokes an increase in cytosolic Ca2+ that can be blocked by the NMDA receptor antagonist AP-5 and by Mg2+. Blocking the activity of these receptors dramatically diminished O-2A cell migration from explants. We also show that NMDA receptor activity is necessary for the expression by O-2A cells of the highly sialylated polysialic acid-neural cell adhesion molecule (PSA-NCAM) that is required for their migration. Thus, glutamate or glutamate receptor ligands may regulate O-2A cell migration by modulating expression of PSA-NCAM. These studies demonstrate how interactions between ionotropic receptors, intracellular signaling, and cell adhesion molecule expression influence cell surface properties, which in turn are critical determinants of cell migration.

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Integrin α9 Suppresses Hepatocellular Carcinoma Metastasis by Rho GTPase Signaling

Journal of Immunology Research ◽

10.1155/2018/4602570 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Yan-Li Zhang ◽

Xin Xing ◽

Li-Bo Cai ◽

Lei Zhu ◽

Xiao-Mei Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Migration ◽

Focal Adhesion ◽

Molecular Mechanisms ◽

Rho Gtpase ◽

Migration And Invasion ◽

Integrin Subunit ◽

Src Tyrosine Kinase ◽

Tumor Cell Migration

Integrin subunit alpha 9 (ITGA9) mediates cell-cell and cell-matrix adhesion, cell migration, and invasion through binding different kinds of extracellular matrix (ECM) components. However, its potential role and underlying molecular mechanisms remain unclear in hepatocellular carcinoma (HCC). Here, we found that ITGA9 expression was obviously decreased in patients with HCC, which was negatively correlated with HCC growth and metastasis. ITGA9 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Our data demonstrated that the inhibitory effect of ITGA9 on HCC cell motility was associated with reduced phosphorylation of focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src), disrupted focal adhesion reorganization, and decreased Rac1 and RhoA activity. Our data suggest ITGA9, as a suppressor of HCC, prevents tumor cell migration and invasiveness through FAK/Src-Rac1/RhoA signaling.

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HDAC6 promotes self-renewal and migration/invasion of rhabdomyosarcoma

10.1101/823864 ◽

2019 ◽

Cited By ~ 1

Author(s):

Thao Q. Pham ◽

Kristin Robinson ◽

Lin Xu ◽

Stephen X. Skapek ◽

Eleanor Y. Chen

Keyword(s):

Cell Migration ◽

Molecular Mechanisms ◽

Therapeutic Option ◽

Migration And Invasion ◽

Survival Outcomes ◽

Self Renewal ◽

Clinical Prognosis ◽

Cell Migration And Invasion ◽

Tumor Cell Migration ◽

And Migration

ABSTRACTRhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. The survival outcomes remain poor for patients with relapsed or metastatic disease. Effective targeted therapy is lacking due to our limited knowledge of the underlying cellular and molecular mechanisms leading to disease progression. In this study, we used functional assays in vitro and in vivo (zebrafish and xenograft mouse models) to demonstrate the crucial role of HDAC6, a cytoplasmic histone deacetylase, in driving RMS tumor growth, self-renewal and migration/invasion. Treatment with the HDAC6-selective inhibitor, Tubastatin A, recapitulates the HDAC6 loss-of-function phenotypes. HDAC6 regulates cytoskeletal dynamics to promote tumor cell migration and invasion. RAC1, a Rho family GTPase, is an essential mediator of HDAC6 function, and is necessary and sufficient for RMS cell migration and invasion. High expression of RAC1 correlates with poor clinical prognosis in RMS patients. Targeting the HDAC6-RAC1 axis represents a promising therapeutic option for improving survival outcomes of RMS patients.

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Activation of Gαi3 triggers cell migration via regulation of GIV

The Journal of Cell Biology ◽

10.1083/jcb.200712066 ◽

2008 ◽

Vol 182 (2) ◽

pp. 381-393 ◽

Cited By ~ 109

Author(s):

Pradipta Ghosh ◽

Mikel Garcia-Marcos ◽

Scott J. Bornheimer ◽

Marilyn G. Farquhar

Keyword(s):

Signal Transduction ◽

Wound Healing ◽

Cell Migration ◽

Mammalian Cells ◽

Leading Edge ◽

Akt Signaling ◽

Actin Remodeling ◽

Tumor Cell Migration ◽

Binding Partner ◽

Macrophage Chemotaxis

During migration, cells must couple direction sensing to signal transduction and actin remodeling. We previously identified GIV/Girdin as a Gαi3 binding partner. We demonstrate that in mammalian cells Gαi3 controls the functions of GIV during cell migration. We find that Gαi3 preferentially localizes to the leading edge and that cells lacking Gαi3 fail to polarize or migrate. A conformational change induced by association of GIV with Gαi3 promotes Akt-mediated phosphorylation of GIV, resulting in its redistribution to the plasma membrane. Activation of Gαi3 serves as a molecular switch that triggers dissociation of Gβγ and GIV from the Gi3–GIV complex, thereby promoting cell migration by enhancing Akt signaling and actin remodeling. Gαi3–GIV coupling is essential for cell migration during wound healing, macrophage chemotaxis, and tumor cell migration, indicating that the Gαi3–GIV switch serves to link direction sensing from different families of chemotactic receptors to formation of the leading edge during cell migration.

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The Cooperative Effect between Polybasic Region (PBR) and Polysialyltransferase Domain (PSTD) within Tumor-Target Polysialyltranseferase ST8Sia II

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191121145924 ◽

2020 ◽

Vol 19 (31) ◽

pp. 2831-2841 ◽

Cited By ~ 3

Author(s):

Guo-Ping Zhou ◽

Si-Ming Liao ◽

Dong Chen ◽

Ri-Bo Huang

Keyword(s):

Conformational Changes ◽

Cancer Metastasis ◽

Intramolecular Interaction ◽

Polysialic Acid ◽

Point Mutations ◽

Amino Acid Residues ◽

Tumor Target ◽

Intrinsic Correlation ◽

Polybasic Domains ◽

Polybasic Region

: ST8Sia II (STX) is a highly homologous mammalian polysialyltransferase (polyST), which is a validated tumor-target in the treatment of cancer metastasis reliant on tumor cell polysialylation. PolyST catalyzes the synthesis of α2,8-polysialic acid (polySia) glycans by carrying out the activated CMP-Neu5Ac (Sia) to N- and O-linked oligosaccharide chains on acceptor glycoproteins. In this review article, we summarized the recent studies about intrinsic correlation of two polybasic domains, Polysialyltransferase domain (PSTD) and Polybasic region (PBR) within ST8Sia II molecule, and suggested that the critical amino acid residues within the PSTD and PBR motifs of ST8Sia II for polysialylation of Neural cell adhesion molecules (NCAM) are related to ST8Sia II activity. In addition, the conformational changes of the PSTD domain due to point mutations in the PBR or PSTD domain verified an intramolecular interaction between the PBR and the PSTD. These findings have been incorporated into Zhou’s NCAM polysialylation/cell migration model, which will provide new perspectives on drug research and development related to the tumor-target ST8Sia II.

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Dissection of the molecular mechanisms of protein targeting to the peroxisome using immunofluorescence and immunocryoelectron microscopies

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100157760 ◽

1990 ◽

Vol 48 (3) ◽

pp. 44-45

Author(s):

G-A. Keller ◽

S. J. Gould ◽

S. Subramani ◽

S. Krisans

Keyword(s):

Mammalian Cells ◽

Molecular Mechanisms ◽

Protein Targeting ◽

Firefly Luciferase ◽

Peroxisomal Enzyme ◽

Transfected Cells ◽

Peroxisomal Targeting ◽

Targeting Signal ◽

Series Of Experiments ◽

Peroxisomal Targeting Signal

Subcellular compartments within eukaryotic cells must each be supplied with unique sets of proteins that must be directed to, and translocated across one or more membranes of the target organelles. This transport is mediated by cis- acting targeting signals present within the imported proteins. The following is a chronological account of a series of experiments designed and carried out in an effort to understand how proteins are targeted to the peroxisomal compartment.-We demonstrated by immunocryoelectron microscopy that the enzyme luciferase is a peroxisomal enzyme in the firefly lantern. -We expressed the cDNA encoding firefly luciferase in mammalian cells and demonstrated by immunofluorescence that the enzyme was transported into the peroxisomes of the transfected cells. -Using deletions, linker insertions, and gene fusion to identify regions of luciferase involved in its transport to the peroxisomes, we demonstrated that luciferase contains a peroxisomal targeting signal (PTS) within its COOH-terminal twelve amino acid.

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