Current Protein and Peptide Science - Volume 12, Issue 1, 2011

Novel Proteins as Regulators of Cell Motility and Invasion Cancer metastasis, one of the hallmarks of malignancy, is the primary cause of death in most cancer patients. Tumor cell migration and invasion are key steps for formation of cancer metastasis. A number of proteins and pathways have been identified to be essential for tumor cell motility and invasion. These proteins therefore represent novel therapeutic targets for the design and development of anticancer drugs. This special issue focuses on several tumor promoters, such as integrin α6β4, c-Met, the mammalian target of rapamycin (mTOR), Rab5, and the focal adhesion kinase (FAK), and tumor suppressors, e.g., the protein phosphatase 2A (PP2A) and the migration and invasion inhibitory protein (MIIP). The selected articles summarize specific aspects of these proteins, including structures, cofactors, regulators, effectors, crosstalk with other signaling molecules/pathways, and highlight their roles in tumor cell migration and invasion, as well as cancer metastasis. Also, the clinical significance of targeting these proteins for cancer treatment and prevention are discussed. PP2A, a Ser/Thr protein phosphatase, is abundantly and ubiquitously expressed, as well as highly conserved during the evolution of eukaryotes. PP2A is a heterotrimeric holoenzyme composed of a catalytic subunit (C subunit), an A subunit (also termed PR65), and members of the B subunit families. The core complex of PP2A consists of the A and C subunits, which are tightly associated and this dimeric core complexes with the regulatory B subunit. The B subunit determines the substrate specificity as well as the spatial and temporal functions of PP2A. Basu reviews the role of PP2A in regulating motility of normal and transformed cells. PP2A may regulate cell motility and invasion, and cancer metastasis by targeting G proteincoupled receptor (GPCR), Akt, the small GTPases epidermal growth factor (EGF) receptor-extracellular signal-regulated kinases (Erk), and focal adhesion proteins. c-Met (Met), a trans-membrane tyrosine kinase receptor, is activated by hepatocyte growth factor (HGF). Steffan et al. summarize the mechanisms driving Met induced tumor cell progression and invasion, the role played by cells in the tumor stroma, and therapeutic approaches to block the receptor activity. Besides, they also highlight two new research areas: 1) attenuation of Met signaling via multiple mechanisms of action targeting tumor cells and cells in the surrounding stroma using plant-derived polyphenols and 2) the induction by HGF of atypical lysosome trafficking, leading to increased protease secretion and tumor cell invasion. These novel findings may help to unveil new therapeutic targets to block the HGF/Met signaling axis to slow cancer progression. mTOR, a Ser/Thr kinase, functions as two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. mTORC1 phosphorylates p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and regulates cell growth, proliferation, survival and motility. mTORC2 phosphorylates Akt, protein kinase C α (PKCα) and the focal adhesion proteins, and controls the activities of the small GTPases (RhoA, Cdc42 and Rac1), and regulates cell survival and the actin cytoskeleton. Zhou and Huang summarize recent findings about mTOR complexes and the role of each component in tumor cell migration and invasion. They also discuss recent advances of rapamycin, a specific inhibitor of mTOR, in inhibition of cell migration, invasion and cancer metastasis. FAK, a non-receptor tyrosine kinase, is crucial for cell migration, proliferation and survival. In response to several types of extracellular ligands, including components of the extracellular matrix and growth factors, FAK is activated. Peng and Guan review the structure and phosphorylation of FAK, the regulation of FAK activity, and the role of FAK in cell migration. They also discuss the roles of FAK in cardiovascular system, nervous system, skin and cancer. Rab5, one of the small GTPases belonging to the Ras superfamily, is best known for its role in regulating the trafficking of early endosomes, Torres and Stupack briefly introduce Rab GTPases, the relationship between Rabs and integrins, the roles of Rab proteins in actin remodeling and cell invasion, as well as cancer progression. Specially, how Rab5 controls cell migration and cancer metastasis is discussed....

Cell motility is a very critical phenomenon that plays an important role in the development of eukaryotic organisms. One of the well studied cell motility phenomena is chemotaxis, which is described as a directional movement of cell in response to changes in external chemotactic gradient. Numerous studies conducted both in unicellular organism and in mammalian cells have demonstrated the importance of phosphatidylionositol-3 kinase (PI3K) in this process. In addition, it is now well established that although PI3K plays an activation role in chemotaxis, the role of phosphatases is also critical to maintain this dynamic cyclical process. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase that is a key player in regulating PI3K signaling. PP2A is abundantly and ubiquitously expressed and has been highly conserved during the evolution of eukaryotes. PP2A is composed of three protein subunits, A, B, and C. Subunit ‘A’ is a 60-65 kDa structural component, ‘C’ is a 36-38 kDa catalytic subunit, and ‘B’ is a 54-130 kDa regulatory subunit. The core complex of PP2A is comprised of the A and C subunits, which are tightly associated and this dimeric core complexes with the regulatory B subunit. The B subunit determines the substrate specificity as well as the spatial and temporal functions of PP2A. PP2A plays an important role in regulating multiple signal transduction pathways, including cell-cycle regulation, cell-growth and development, cytoskeleton dynamics, and cell motility. This review focuses on the role of PP2A in regulating motility of normal and transformed cells.

The Met tyrosine kinase receptor is the only known receptor for hepatocyte growth factor (HGF). Downstream Met signaling is essential for embryonic development; however, aberrant Met signaling promotes tumor progression by facilitating cell proliferation, survival, migration, invasion, and metastasis. Tumor cell invasion is considered an important step in distant metastatic foci formation. Several recent reviews have focused on the pleiotropic effects of Met signaling in both tumor cells and in the surrounding stromal cells. This review will summarize the currently described mechanisms driving Met induced tumor cell progression and invasion, the role played by cells in the tumor stroma, and therapeutic approaches to block receptor activity. In addition, this review will also highlight two new areas of development: 1) attenuation of Met signaling via multiple mechanisms of action targeting tumor cells and cells in the surrounding stroma using plant-derived polyphenols and 2) the induction by HGF of atypical lysosome trafficking, leading to increased protease secretion and tumor cell invasion. These new areas of research will help to uncover novel therapeutic targets to block the HGF/Met signaling axis to slow cancer progression.

Integrin α6β4 is the receptor for the laminin family of extracellular matrix proteins and is widely expressed in most epithelial tissues and Schwann cells. The expression of this integrin is up-regulated in most epithelial tumors, suggesting the role of α6β4 in their progression. The tumor microenvironment is also known to enhance the signaling competence of α6β4 through functional and physical interactions with other receptors. In this review, we discuss the biological mechanisms by which integrin α6β4 promotes carcinoma cell motility and invasion that leads to mammary tumor progression.

Tumor cell migration and invasion play fundamental roles in cancer metastasis. The mammalian target of rapamycin (mTOR), a highly conserved and ubiquitously expressed serine/threonine (Ser/Thr) kinase, is a central regulator of cell growth, proliferation, differentiation and survival. Recent studies have shown that mTOR also plays a critical role in the regulation of tumor cell motility, invasion and cancer metastasis. Current knowledge indicates that mTOR functions as two distinct complexes, mTORC1 and mTORC2. mTORC1 phosphorylates p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and regulates cell growth, proliferation, survival and motility. mTORC2 phosphorylates Akt, protein kinase C α (PKCα) and the focal adhesion proteins, and controls the activities of the small GTPases (RhoA, Cdc42 and Rac1), and regulates cell survival and the actin cytoskeleton. Here we briefly review recent knowledge of mTOR complexes and the role of mTOR signaling in tumor cell migration and invasion. We also discuss recent efforts about the mechanism by which rapamycin, a specific inhibitor of mTOR, inhibits cell migration, invasion and cancer metastasis.

Cellular invasion requires careful regulation of the cell migration and apoptotic signaling cascades, allowing cell movement and survival of the emigrating populations. Components of the endosomal machinery are involved in these processes, and in particular the role of small GTPases of the Rab family has become appreciated. Rab5 is best known for its role in regulating the trafficking of early endosomes, however, it has recently been appreciated to associate with and regulate the routing of complexes containing integrins, the primary cellular receptors for the extracellular matrix. The association regulates the spatio-temporal activation of signals of downstream growth factors and integrins. Rab proteins have also been linked to apoptosis mediated by cell surface death receptors, which elicit the activation of the death cascade via activation of caspase-8. Recently, the link between trafficking, apoptosis and cell migration was strengthened, as Rab5 was determined to work in conjunction with caspase-8 in promoting tumor cell motility and metastasis by regulating β1 integrin traffic. The capacity to connect and regulate these pathways identifies Rab5 as a key player in future studies of cell migration and tumor dissemination.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that has been shown to have key roles in cell migration, proliferation and survival. FAK activity can be stimulated in response to several types of extracellular ligands, including components of the extracellular matrix and growth factors, suggesting that FAK is an important integrator of multiple cues in the extracellular milieu. Recently, major progress has been made in understanding the molecular mechanisms regulating FAK activity. In particular, several novel proteins have been identified that can bind to FAK and inhibit its activity and associated cellular functions, including cell motility and invasion. Consistent with its critical functions in signal transduction, FAK also plays a pivotal role in mouse development. The inactivation of FAK in mice results in embryonic lethality around E8.5; this early embryonic lethal phenotype limits the use of the FAK total knockout mouse model for studying FAK function in later embryonic development stages and in adult mice. To overcome this problem, three independent groups created FAK/flox mice and generated several different FAK tissue-specific knockout mice models. Here we summarize the progress that has been made regarding the regulation of FAK-mediated signaling events in cell-based systems and also highlight the in vivo functions of FAK in a number of terminally differentiated cell lineages, including vascular endothelial cells, cardiomyocytes, neuronal cells, keratinocytes and several cancerous cell types.

The migration and invasion inhibitory protein (MIIP) was initially discovered in a yeast two-hybrid screen for proteins that interact and inhibit the migration and invasion-promoting protein insulin-like growth factor binding protein 2 (IGFBP2). Recent studies have shown that MIIP not only modulates IGFBP2 but also regulates microtubule by binding to and inhibiting HDAC6, a class 2 histone deacetylase that deacetylates -tubulin, heat-shock protein 90 (HSP90), and cortactin. In addition, MIIP also regulates the mitosis checkpoint, another microtubule-associated process. The location of the MIIP gene in chromosomal region 1p36, a commonly deleted region in a broad spectrum of human cancers, and the observation that MIIP attenuates tumorigenesis in a mouse model suggest that it functions as a tumor-suppressor gene. This review summarizes the recent progress in characterizing this novel protein, which regulates cell migration and mitosis, two processes that rely on the highly coordinated dynamics of the microtubule and cytoskeleton systems.