Table of Contents

Volume 6, Issue 4

  July/August 2012

  Pages 297 - 384

Susann Brady-Kalnay (Department of Molecular Biology and Microbiology; Case Western Reserve University; Cleveland, OH USA), with valuable assistance from Sonya Craig, served as Guest Editor for this issue's special focus series on molecular mechanisms of cancer cell-cell interactions.

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COMMENTARIES

Burkholderia cenocepacia infection: Disruption of phagocyte immune functions through Rho GTPase inactivation

Ronald S. Flannagan
Pages 297 - 301
http://dx.doi.org/10.4161/cam.20487
Abstract | Full Text | PDF

Phagocytosis is an important component of innate immunity that contributes to the eradication of infectious microorganisms; however, successful bacterial pathogens often evade different aspects of host immune responses. A common bacterial evasion strategy entails the production of toxins and/or effectors that disrupt normal host cell processes and because of their importance Rho-family GTPases are often targeted. Burkholderia cenocepacia, an opportunistic pathogen that has a propensity to infect cystic fibrosis patients, is an example of a pathogenic bacterium that has only recently been shown to disrupt Rho GTPase function in professional phagocytes. More specifically, B. cenocepacia disrupts Rac and Cdc42 seemingly through perturbation of guanine nucleotide exchange factor function. Inactivation of Rac, Cdc42 and conceivably other Rho GTPases seriously compromises phagocyte function.

Open Access Article

Integrin adhesions: Who’s on first? What's on second?: Connections between FAK and talin

Christine Lawson and David D. Schlaepfer
Pages 302 - 306
http://dx.doi.org/10.4161/cam.20488
Abstract | Full Text | PDF

Cell migration requires the coordination of adhesion site assembly and turnover. Canonical models for nascent adhesion formation postulate that integrin binding to extracellular matrix (ECM) proteins results in the rapid recruitment of cytoskeletal proteins such as talin and paxillin to integrin cytoplasmic domains. It is thought that integrin-talin clusters recruit and activate tyrosine kinases such as focal adhesion kinase (FAK). However, the molecular connections of this linkage remain unresolved. Our recent findings support an alternative model whereby FAK recruits talin to new sites of β1 integrin-mediated adhesion in mouse embryonic fibroblasts and human ovarian carcinoma cells. This is dependent on a direct binding interaction between FAK and talin and occurs independently of direct talin binding to β1 integrin. Herein, we discuss differences between nascent and mature adhesions, interactions between FAK, talin and paxillin, possible mechanisms of FAK activation and how this FAK-talin complex may function to promote cell motility through increased adhesion turnover.

DPP in the matrix mediates cell adhesion but is not restricted to stickiness: A tale of signaling

Asha Eapen, Amsaveni Ramachandran and Anne George
Pages 307 - 311
http://dx.doi.org/10.4161/cam.20627
Abstract | Full Text | PDF

Cell adhesion to DPP substrate is an integrin-mediated event and involves integrin binding, clustering, assembly of focal adhesion complexes and cytoskeletal organization. Cells perceive the DPP substrate through the integrin receptor αvβ1 and bind the actin cytoskeleton to the membrane via focal adhesion sites. The cells respond to this proteinaceous rigid substrate by activating the mechano-chemical signaling events leading to cell spreading and formation of focal adhesions. Focal adhesions, which are sites of integrin binding to the extracellular matrix, form in the leading edge during cell migration. These sites are dynamic and the supramolecular assemblies contain structural and signaling components regulating cell functions. In our study, we present a scenario that integrins utilize the actin network to permit activation of the mitogen-activated kinase modules to transduce signals through the cytoplasm to the nucleus in the presence of DPP. We specifically demonstrate that ERK-mediated transcriptional events impinge on activation of transcription factors leading to cell differentiation.

Open Access Article

IGF2BP1: A post-transcriptional “driver” of tumor cell migration

Nadine Stöhr and Stefan Hüttelmaier
Pages 312 - 318
http://dx.doi.org/10.4161/cam.20628
Abstract | Full Text | PDF

The oncofetal RNA-binding protein IGF2BP1 (IGF2 mRNA binding protein 1) controls the cytoplasmic fate of specific target mRNAs including ACTB and CD44. During neural development, IGF2BPs promote neurite protrusion and the migration of neuronal crest cells. In tumor-derived cells, IGF2BP1 enhances the formation of lamellipodia and invadopodia. Accordingly, the de novo synthesis of IGF2BP1 observed in primary malignancies was reported to correlate with increased metastasis and an overall poor prognosis. However, if and how the protein enhances metastasis remains controversial. In recent studies, we reveal that IGF2BP1 promotes the directed migration of tumor-derived cells in vitro by controlling the expression of MAPK4 and PTEN. The IGF2BP1-facilitated inhibition of MAPK4 mRNA translation interferes with MK5-directed phosphorylation of the heat shock protein 27 (HSP27). This limits G-actin sequestering by phosphorylated HSP27, enhances cell adhesion and elevates the velocity of tumor cell migration. Concomitantly, IGF2BP1 promotes the expression of PTEN by interfering with PTEN mRNA turnover. This results in a shift of cellular PtdIns(3,4,5)P₃/PtdIns(4,5)P₂ ratios and enhances RAC1-dependent cell polarization which finally promotes the directionality of tumor cell migration. These findings identify IGF2BP1 as a potent oncogenic factor that regulates the adhesion, migration and invasiveness of tumor cells by modulating intracellular signaling.

Functional significance of periostin in excisional skin repair: Is the devil in the detail?

Christopher G. Elliott, Shawna S. Kim and Douglas W. Hamilton
Pages 319 - 326
http://dx.doi.org/10.4161/cam.20879
Abstract | Full Text | PDF

In the past year, three papers have been published exploring the role of the matricellular protein periostin in excisional skin repair. These papers all show a delay in wound closure and the kinetics of this delay are strikingly similar across the three reports. The similarities between these papers end, however, when each investigates the mechanism through which periostin influences skin repair. Three proposed mechanisms have been identified: (1) myofibroblast differentiation, (2) keratinocyte proliferation and (3) fibroblast proliferation and migration. The aim of this commentary is to compare and contrast the three studies performed to date in an attempt to decipher the role of periostin in the repair of full-thickness skin wounds.

N-cadherin expression level as a critical indicator of invasion in non-epithelial tumors

Florent Péglion and Sandrine Etienne-Manneville
Pages 327 - 332
http://dx.doi.org/10.4161/cam.20855
Abstract | Full Text | PDF

Cancer cell dissemination away from the primary tumor and their ability to form metastases remain the major causes of death from cancer. Understanding the molecular mechanisms triggering this event could lead to the design of new cancer treatments. The establishment and the maintenance of tissue architecture depend on the coordination of cell behavior within this tissue. Cell-cell interactions must form adhesive structures between neighboring cells while remaining highly dynamic to allow and control tissue renewal or remodeling. Among intercellular junctions, cadherin-based adherens junctions mediate strong physical interactions and transmit information from the cell microenvironment to the cytoplasm. Disruption of these cell-cell contacts perturbs the polarity of epithelial tissues leading to their disorganization and ultimately to aggressive carcinomas. In non-epithelial tissues, the role of cadherins in the development of cancer is still debated. We recently found that downregulation of N-cadherin in malignant glioma—the most frequent primary brain tumor—results in cell polarization defects leading to abnormal motile behavior with increased cell speed and decreased persistence in directionality. Re-expression of N-cadherin in glioma cells restores cell polarity and limits glioma cell migration, providing a potential therapeutic tool for diffuse glioma.




RESEARCH PAPER

Wip1 phosphatase positively modulates dendritic spine morphology and memory processes through the p38MAPK signaling pathway

Francesca Fernandez, Irene Soon, Zeng Li, Tan Chee Kuan, Deng Hong Min, Esther Sook-Miin Wong, Oleg N. Demidov, Malcolm C. Paterson, Gavin Dawe, Dmitry V. Bulavin and Zhi-Cheng Xiao
Pages 333 - 343
http://dx.doi.org/10.4161/cam.20892
Abstract | Full Text | PDF

Dendritic spine morphology is modulated by protein kinase p38, a mitogen-activated protein (MAPK), in the hippocampus. Protein p38MAPK is a substrate of wip1, a protein phosphatase. The role of wip1 in the central nervous system (CNS) has never been explored. Here, we report a novel function of wip1 in dendritic spine morphology and memory processes. Wip1 deficiency decreases dendritic spine size and density in pyramidal neurons of the hippocampal CA1 region. Simultaneously, impairments in object recognition tasks and contextual memory occur in wip1 deficient mice, but are reversed in wip1/p38 double mutant mice. Thus, our findings demonstrate that wip1 modulates dendritic morphology and memory processes through the p38MAPK signaling pathway. In addition to the well-characterized role of the wip1/p38MAPK in cell death and differentiation, we revealed the novel contribution of wip1 to cognition and dendritic spine morphology, which may suggest new approaches to treating neurodegenerative disorders.





Special Focus: Molecular Mechanisms of Cancer Cell-Cell Interactions

LETTER FROM THE GUEST EDITOR

Molecular mechanisms of cancer cell-cell interactions: Cell-cell adhesion-dependent signaling in the tumor microenvironment

Susann M. Brady-Kalnay
Pages 344 - 345
http://dx.doi.org/10.4161/cam.21489
Full Text | PDF

REVIEWS

The malignant social network: Cell-cell adhesion and communication in cancer stem cells

James S. Hale, Meizhang Li and Justin D. Lathia
Pages 346 - 355
http://dx.doi.org/10.4161/cam.21294
Abstract | Full Text | PDF

Tumors contain a vastly complicated cellular network that relies on local communication to execute malignant programs. The molecular cues that are involved in cell-cell adhesion orchestrate large-scale tumor behaviors such as proliferation and invasion. We have recently begun to appreciate that many tumors contain a high degree of cellular heterogeneity and are organized in a cellular hierarchy, with a cancer stem cell (CSC) population identified at the apex in multiple cancer types. CSCs reside in unique microenvironments or niches that are responsible for directing their behavior through cellular interactions between CSCs and stromal cells, generating a malignant social network. Identifying cell-cell adhesion mechanisms in this network has implications for the basic understanding of tumorigenesis and the development of more effective therapies. In this review, we will discuss our current understanding of cell-cell adhesion mechanisms used by CSCs and how these local interactions have global consequences for tumor biology.

Receptor protein tyrosine phosphatases and cancer: New insights from structural biology

Roman M. Nikolaienko, Boadi Agyekum and Samuel Bouyain
Pages 356 - 364
http://dx.doi.org/10.4161/cam.21242
Abstract | Full Text | PDF

There is general agreement that many cancers are associated with aberrant phosphotyrosine signaling, which can be caused by the inappropriate activities of tyrosine kinases or tyrosine phosphatases. Furthermore, incorrect activation of signaling pathways has been often linked to changes in adhesion events mediated by cell surface receptors. Among these receptors, receptor protein tyrosine phosphatases (RPTPs) both antagonize tyrosine kinases as well as engage extracellular ligands. A recent wealth of data on this intriguing family indicates that its members can fulfill either tumor suppressing or oncogenic roles. The interpretation of these results at a molecular level has been greatly facilitated by the recent availability of structural information on the extra- and intracellular regions of RPTPs. These structures provide a molecular framework to understand how alterations in extracellular interactions can inactivate RPTPs in cancers or why the overexpression of certain RPTPs may also participate in tumor progression.

The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression

Grégoire F. Le Bras, Kenneth J. Taubenslag and Claudia D. Andl
Pages 365 - 373
http://dx.doi.org/10.4161/cam.21326
Abstract | Full Text | PDF

Adherens junctions (AJs) are essential for the maintenance of epithelial homeostasis and a key factor in the regulation of cell migration and tumor progression. AJs maintain cell-cell adhesion by linking transmembrane proteins to the actin cytoskeleton. Additionally, they participate in recruitment of signaling receptors and cytoplasmic proteins to the membrane. During cellular invasion or migration, AJs are dynamically regulated and their composition modified to initiate changes in signaling pathways and cytoskeleton organization involved in cellular motility. Loss of E-cadherin, a key component of AJs, is characteristic of epithelial-mesenchymal-transition (EMT) and is associated with tumor cell invasion. We will review recent findings describing novel mechanisms involved in E-cadherin transcription regulation, endocytosis of E-cadherin and signaling associated with loss of AJs as well as reorganization of the AJ during EMT.

L1CAM: A major driver for tumor cell invasion and motility

Helena Kiefel, Sandra Bondong, John Hazin, Johannes Ridinger, Uwe Schirmer, Svenja Riedle and Peter Altevogt
Pages 374 - 384
http://dx.doi.org/10.4161/cam.20832
Abstract | Full Text | PDF

The L1 cell adhesion molecule (L1CAM) plays a major role in the development of the nervous system and in the malignancy of human tumors. In terms of biological function, L1CAM comes along in two different flavors: (1) a static function as a cell adhesion molecule that acts as a glue between cells; (2) a motility promoting function that drives cell migration during neural development and supports metastasis of human cancers. Important factors that contribute to the switch in the functional mode of L1CAM are: (1) the cleavage from the cell surface by membrane proximal proteolysis and (2) the ability to change binding partners and engage in L1CAM-integrin binding. Recent studies have shown that the cleavage of L1CAM by metalloproteinases and the binding of L1CAM to integrins via its RGD-motif in the sixth Ig-domain activate signaling pathways distinct from the ones elicited by homophilic binding. Here we highlight important features of L1CAM proteolysis and the signaling of L1CAM via integrin engagement. The novel insights into L1CAM downstream signaling and its regulation during tumor progression and epithelial-mesenchymal transition (EMT) will lead to a better understanding of the dualistic role of L1CAM as a cell adhesion and/or motility promoting cell surface molecule.