Tenascin-C in the early lung cancer tumor microenvironment promotes progression through integrin αvβ1 and FAK.

Pre-cancerous lung lesions are commonly initiated by activating mutations in the RAS pathway, but do not transition to lung adenocarcinomas (LUAD) without additional oncogenic signals. Here, we show that expression of the extracellular matrix protein Tenascin-C (TNC) is increased in and promotes the earliest stages of LUAD development in oncogenic KRAS-driven lung cancer mouse models and in human LUAD. TNC is initially expressed by fibroblasts and its expression extends to tumor cells as the tumor becomes invasive.

Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration.

Lasso peptides are a structurally distinct class of biologically active natural products defined by their short sequences with impressively interlocked tertiary structures. Their characteristic peptide [1]rotaxane motif confers marked proteolytic and thermal resiliency, and reports on their diverse biological functions have been credited to their exceptional sequence variability. Because of these unique properties, taken together with improved technologies for their biosynthetic production, lasso peptides are emerging as a designable scaffold for peptide-based therapeutic discovery and development.

Nascent adhesions shorten the period of lamellipodium protrusion through the Brownian ratchet mechanism.

Directional cell migration is driven by the conversion of oscillating edge motion into lasting periods of leading edge protrusion. Actin polymerization against the membrane and adhesions control edge motion, but the exact mechanisms that determine protrusion period remain elusive. We addressed this by developing a computational model in which polymerization of actin filaments against a deformable membrane and variable adhesion dynamics support edge motion.

Computational model of integrin adhesion elongation under an actin fiber.

Cells create physical connections with the extracellular environment through adhesions. Nascent adhesions form at the leading edge of migrating cells and either undergo cycles of disassembly and reassembly, or elongate and stabilize at the end of actin fibers. How adhesions assemble has been addressed in several studies, but the exact role of actin fibers in the elongation and stabilization of nascent adhesions remains largely elusive.

Mechanics of lung cancer: A finite element model shows strain amplification during early tumorigenesis.

Early lung cancer lesions develop within a unique microenvironment that undergoes constant cyclic stretch from respiration. While tumor stiffening is an established driver of tumor progression, the contribution of stress and strain to lung cancer is unknown. We developed tissue scale finite element models of lung tissue to test how early lesions alter respiration-induced strain.

ERK signaling for cell migration and invasion.

The RAS - Extracellular signal-regulated kinase (RAS-ERK) pathway plays a conserved role in promoting cell migration and invasion. Growth factors, adhesion, and oncogenes activate ERK. While historically studied with respect to its control of cell proliferation and differentiation, the signaling pattern and effectors specific for cell migration are now coming to light.

NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity.

The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear.

An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma.

Cancer cells undergo lineage switching during natural progression and in response to therapy. NKX2-1 loss in human and murine lung adenocarcinoma leads to invasive mucinous adenocarcinoma (IMA), a lung cancer subtype that exhibits gastric differentiation and harbors a distinct spectrum of driver oncogenes. In murine BRAF-driven lung adenocarcinoma, NKX2-1 is required for early tumorigenesis, but dispensable for established tumor growth.

p90 ribosomal S6 kinase (RSK) phosphorylates myosin phosphatase and thereby controls edge dynamics during cell migration.

Cell migration is essential to embryonic development, wound healing, and cancer cell dissemination. Cells move via leading-edge protrusion, substrate adhesion, and retraction of the cell's rear. The molecular mechanisms by which extracellular cues signal to the actomyosin cytoskeleton to control these motility mechanics are poorly understood.

AKT1 Activates Focal Adhesion Kinase and Promotes Melanoma Brain Metastasis.

Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear.

Violent relationships at the social-ecological level: A multi-mediation model to predict adolescent victimization by peers, bullying and depression in early and late adolescence.

Background: From the social-ecological perspective, exposure to violence at the different developmental levels is fundamental to explain the dynamics of violence and victimization in educational centers. The following study aims at analyzing how these relationships are produced in the Peruvian context, where structural violence situations exist.

Methods: A multi-mediation structural model with 21,416 Peruvian adolescents (M = 13.

ERK reinforces actin polymerization to power persistent edge protrusion during motility.

Cells move through perpetual protrusion and retraction cycles at the leading edge. These cycles are coordinated with substrate adhesion and retraction of the cell rear. We tracked spatial and temporal fluctuations in the molecular activities of individual moving cells to elucidate how extracellular signal-regulated kinase (ERK) signaling controlled the dynamics of protrusion and retraction cycles.

AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve.

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that controls cell proliferation, growth, survival, metabolism, and migration by activating the PI3K (phosphatidylinositol 3-kinase)-AKT and ERK (extracellular signal-regulated kinase)-RSK (ribosomal S6 kinase) pathways. EGFR signaling to these pathways is temporally and spatially regulated. Endocytic trafficking controls the access of EGFR to these downstream effectors and also its degradation, which terminates EGFR signaling.

Phosphoregulation of the WAVE regulatory complex and signal integration.

The WAVE2 regulatory complex (WRC) induces actin polymerization by activating the actin nucleator Arp2/3. Polymerizing actin pushes against the cell membrane and induces dramatic edge protrusions. In order to properly control such changes in cell morphology and function, cells have evolved multiple methods to tightly regulate WRC and Arp2/3 activity in space and time.

Quantitative fluorescent speckle microscopy (QFSM) to measure actin dynamics.

Quantitative fluorescent speckle microscopy (QFSM) is a live-cell imaging method to analyze the dynamics of macromolecular assemblies with high spatial and temporal resolution. Its greatest successes were in the analysis of actin filament and adhesion dynamics in the context of cell migration and microtubule dynamics in interphase and the meiotic/mitotic spindle. Here, focus is on the former application to illustrate the procedures of FSM imaging and the computational image processing that extracts quantitative information from these experiments.

Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase (ERK) signaling.

The acquisition of an invasive phenotype is a critical turning point for malignant tumor cells. CMTM8, a potential tumor suppressor, is frequently down-regulated in solid tumors, and its overexpression induces tumor cell apoptosis. Here, we identify a new role for CMTM8 in regulating tumor cell migration.

The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation.

The Ras-extracellular signal-regulated kinase (Ras-ERK) and phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR) signaling pathways are the chief mechanisms for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. Components of these pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Ras-ERK and PI3K-mTOR were originally modeled as linear signaling conduits activated by different stimuli, yet even early experiments hinted that they might intersect to regulate each other and co-regulate downstream functions.

ERK-MAPK drives lamellipodia protrusion by activating the WAVE2 regulatory complex.

Cell movement begins with a leading edge protrusion, which is stabilized by nascent adhesions and retracted by mature adhesions. The ERK-MAPK (extracellular signal-regulated kinase-mitogen-activated protein kinase) localizes to protrusions and adhesions, but how it regulates motility is not understood. We demonstrate that ERK controls protrusion initiation and protrusion speed.

ERK-MAP Kinase signaling in the cytoplasm.

ERK-MAPK is activated by dual phosphorylation of its activation loop TEY motif by the MEK-MAPKK. ERK cytoplasmic activity should be measured by assaying both the level of dually phosphorylated ERK and the level of phosphorylated substrate. We describe two complementary methods for quantitatively measuring ERK activity toward the cytoplasmic p90 ribosomal S6 kinase (RSK).

p90 ribosomal S6 kinase and p70 ribosomal S6 kinase link phosphorylation of the eukaryotic chaperonin containing TCP-1 to growth factor, insulin, and nutrient signaling.

Chaperonin containing TCP-1 (CCT) is a large multisubunit complex that mediates protein folding in eukaryotic cells. CCT participates in the folding of newly synthesized polypeptides, including actin, tubulin, and several cell cycle regulators; therefore, CCT plays an important role in cytoskeletal organization and cell division. Here we identify the chaperonin CCT as a novel physiological substrate for p90 ribosomal S6 kinase (RSK) and p70 ribosomal S6 kinase (S6K).

PHLPPing it off: phosphatases get in the Akt.

Three Akt isoforms differentially control cell survival, growth, proliferation, metabolism, and motility. In this issue of Molecular Cell, Brognard et al. (2007) report that two PHLPP phosphatases specifically downregulate the Akts to control the activity of isoform-specific substrates.

MEK1 and protein phosphatase 4 coordinate Dictyostelium development and chemotaxis.

The MEK and extracellular signal-regulated kinase/mitogen-activated protein kinase proteins are established regulators of multicellular development and cell movement. By combining traditional genetic and biochemical assays with a statistical analysis of global gene expression profiles, we discerned a genetic interaction between Dictyostelium discoideum mek1, smkA (named for its role in the suppression of the mek1(-) mutation), and pppC (the protein phosphatase 4 catalytic subunit gene). We found that during development and chemotaxis, both mek1 and smkA regulate pppC function.

Assaying chemotaxis of Dictyostelium cells.

Both prokaryote and eukaryote cells can sense and move up chemical concentration gradients (chemotax). As a means of finding food sources during vegetative growth, Dictyostelium discoideum naturally chemotaxes toward chemicals released by bacteria. As part of its developmental life cycle, D.

Loss of SMEK, a novel, conserved protein, suppresses MEK1 null cell polarity, chemotaxis, and gene expression defects.

MEK/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase signaling is imperative for proper chemotaxis. Dictyostelium mek1(-) (MEK1 null) and erk1(-) cells exhibit severe defects in cell polarization and directional movement, but the molecules responsible for the mek1(-) and erk1(-) chemotaxis defects are unknown. Here, we describe a novel, evolutionarily conserved gene and protein (smkA and SMEK, respectively), whose loss partially suppresses the mek1(-) chemotaxis phenotypes.