oa Editorial [Hot Topic: Novel Protein & Peptide Science (Guest Editor: Shile Huang)]

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....