Malignant cancer cells utilize their intrinsic migratory ability to invade adjacent tissues and the vasculature, and ultimately to metastasize. Cell migration is the sum of multi-step processes initiated by the formation of membrane protrusions in response to migratory and chemotactic stimuli. The driving force for membrane protrusion is localized polymerization of submembrane actin filaments. Recently, several studies revealed that molecules that link migratory signals to the actin cytoskeleton are upregulated in invasive and metastatic cancer cells. In this review, we summarize recent progress on molecular mechanisms of formation of invasive protrusions used by tumor cells, such as lamellipodia and invadopodia, with regard to the functions of key regulatory proteins of the actin cytoskeleton; WASP family proteins, Arp2/3 complex, LIM-kinase, cofilin, and cortactin.

We determined the immunohistochemical distributions of orexin-A and orexin-B, hypothalamic peptides that function in the regulation of feeding behavior and energy homeostasis. Orexin-A and -B neurons were restricted to the lateral and posterior hypothalamus, whereas both orexin-A and -B nerve fibers projected widely into the olfactory bulb, cerebral cortex, thalamus, hypothalamus, and brainstem. Dense populations of orexin-containing fibers were present in the paraventricular thalamic nucleus, central gray, raphe nuclei, and locus coeruleus. Moderate numbers of these fibers were found in the olfactory bulb, insular, infralimbic and prelimbic cortex, amygdala, ventral, and dorsolateral parts of the suprachiasmatic nucleus, paraventricular nucleus except the lateral magnocellular division, arcuate nucleus, supramammillary nucleus, nucleus of the solitary tract, and dorsal motor nucleus of the vagus. Small numbers of orexin fibers were present in the perirhinal, motor and sensory cortex, hippocampus, and supraoptic nucleus, and a very small number in the lateral magnocellular division of the paraventricular nucleus. Intracerebroventricular injections of orexins induced c-fos expression in the paraventricular thalamic nucleus, locus coeruleus, arcuate nucleus, central gray, raphe nuclei, nucleus of the solitary tract, dorsal motor nucleus of the vagus, suprachiasmatic nucleus, supraoptic nucleus, and paraventricular nucleus except the lateral magnocellular division. The unique neuronal distribution of orexins and their functional activation of neural circuits suggest specific complex roles of the peptides in autonomic and neuroendocrine control.The lateral hypothalamus (LH) is a region classically implicated in the central regulation of feeding behavior and energy homeostasis (1-3). Feeding behavior is regulated by a large number of substances, including peptides, whereas, until the discovery of orexins, melanin-concentrating hormone (MCH) was the only neuropeptide known to be synthesized specifically in the LH and zona incerta and to stimulate food intake (4, 5). Very recently, two novel hypothalamic peptides named orexin-A and orexin-B (from the Greek word for appetite, orexis) were discovered in an intracellular calcium influx assay on multiple cells expressing individual ''orphan'' G proteincoupled receptors (6). Orexin-A is a 33-residue peptide with two intramolecular disulfide bonds in the N-terminal region, and orexin-B is a linear 28-residue peptide. These peptides, encoded by a single mRNA transcript, have a 46% amino acid sequence identity. This mRNA also was found in rat hypothalamus by another group of researchers using the directional tag PCR subtraction method (7). Bolus injections of orexin-A and -B to rat lateral ventricle stimulated food intake dose dependently (6). prepro-orexin mRNA was restricted to the LH and adjacent areas, and its mRNA level up-regulated on fasting (6). Orexins therefore are thought to participate in the hypothalamic regulation of feeding behavior. Better understanding...

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Invadopodia are matrix-degrading membrane protrusions in invasive carcinoma cells. The mechanisms regulating invadopodium assembly and maturation are not understood. We have dissected the stages of invadopodium assembly and maturation and show that invadopodia use cortactin phosphorylation as a master switch during these processes. In particular, cortactin phosphorylation was found to regulate cofilin and Arp2/3 complex–dependent actin polymerization. Cortactin directly binds cofilin and inhibits its severing activity. Cortactin phosphorylation is required to release this inhibition so cofilin can sever actin filaments to create barbed ends at invadopodia to support Arp2/3-dependent actin polymerization. After barbed end formation, cortactin is dephosphorylated, which blocks cofilin severing activity thereby stabilizing invadopodia. These findings identify novel mechanisms for actin polymerization in the invadopodia of metastatic carcinoma cells and define four distinct stages of invadopodium assembly and maturation consisting of invadopodium precursor formation, actin polymerization, stabilization, and matrix degradation.