Metastasis is the primary cause of death in most human cancers, and understanding the molecular mechanisms underpinning this multistep process is fundamental to identifying novel molecular targets and developing more effective therapies. Growth Factor Receptor-bound protein 2 (Grb2) is a key molecule in intracellular signal transduction, linking activated cell surface receptors to downstream targets by binding to specific phosphotyrosine-containing and proline-rich sequence motifs. Grb2 signaling is critical for cell cycle progression and actin-based cell motility, and consequently, more complex processes such as epithelial morphogenesis, angiogenesis and vasculogenesis. These important functions make Grb2 a logical therapeutic target for strategies designed to prevent the spread of solid tumors through local invasion and metastasis. Here we review the role of Grb2 in cancer and specifically in metastasis-related processes, and summarize briefly the development of anti-cancer therapeutics selectively targeting this important adapter protein.

The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation.

Purpose: Many proteins are proteolytically released from the cell surface by a process known as ectodomain shedding. Shedding occurs under normal physiologic conditions and can be increased in certain pathologies. Among the many receptors for which ectodomain shedding has been shown is c-Met, the hepatocyte growth factor (HGF) receptor tyrosine kinase. HGF stimulates mitogenesis, motogenesis, and morphogenesis in a variety of cellular targets during development, homeostasis, and tissue regeneration. Inappropriate HGF signaling resulting in unregulated cell proliferation, motility, and invasion occurs in several human malignancies. This can occur through paracrine signaling, autocrine loop formation, receptor mutation, gene amplification, or gene rearrangement, accompanied frequently with overexpression of ligand and/or receptor proteins.We hypothesized that c-Met overexpression in cancer might result in increased ectodomain shedding, and that its measure could be a useful biomarker of tumor progression. Experimental Design: We developed a sensitive electrochemiluminescent immunoassay to quantitate c-Met protein in cell lysates, culture supernatants, and biological samples. Results: A survey of cultured cell models of oncogenic transformation revealed significant direct correlations (P < 0.001, t test orANOVA) between malignant potential and the rate of c-Met ectodomain shedding that was independent of steady-state receptor expression level. Moreover, weekly plasma and urine samples from mice harboring s.c. human tumor xenografts (n = 4 per group) displayed soluble human c-Met levels that were measurable before tumors became palpable and that correlated directly with tumor volume (R 2 > 0.92, linear regression).Conclusions: For a variety of human cancers, c-Met ectodomain shedding may provide a reliable and practical indicator of malignant potential and overall tumor burden.

The melanocortin-1 receptor (MC1R) is a key regulator of pigmentation in mammals and is tightly linked to an increased risk of skin cancers, including melanoma, in humans. Physiologically activated by ␣-melanocyte stimulating hormone (␣MSH), MC1R function can be antagonized by a secreted factor, agouti signal protein (ASP), which is responsible for the lighter phenotypes in mammals (including humans), and is also associated with increased risk of skin cancer. It is therefore of great interest to characterize the molecular effects elicited by those MC1R ligands. In this study, we determined the gene expression profiles of murine melan-a melanocytes treated with ASP or ␣MSH over a 4-day time course using genome-wide oligonucleotide microarrays. As expected, there were significant reductions in expression of numerous melanogenic proteins elicited by ASP, which correlates with its inhibition of pigmentation. ASP also unexpectedly modulated the expression of genes involved in various other cellular pathways, including glutathione synthesis and redox metabolism. Many genes up-regulated by ASP are involved in morphogenesis (especially in nervous system development), cell adhesion, and extracellular matrix-receptor interactions. Concomitantly, ASP enhanced the migratory potential and the invasiveness of melanocytic cells in vitro. These results demonstrate the role of ASP in the dedifferentiation of melanocytes, identify pigment-related genes targeted by ASP and by ␣MSH, and provide insights into the pleiotropic molecular effects of MC1R signaling that may function during development and may affect skin cancer risk.pigmentation ͉ skin cancer A major determinant of the pigment phenotype of the skin is the melanocortin-1 receptor (MC1R), a G protein coupled receptor (GPCR) that regulates many functional aspects of melanocytes, including their dendricity, melanogenesis, and proliferation (1, 2). MC1R function can be activated by ␣-melanocyte-stimulating hormone (␣MSH), a POMC-derived peptide whose production in the skin (3) is increased by exposure to UV radiation (UV) via a p53-dependent mechanism (4). This interaction triggers increased melanin production (5, 6) and stimulates the repair of DNA photoproducts caused by UV (7-9), a phenomenon also induced by forskolin (10). It is therefore not surprising that MC1R polymorphisms are associated with a lighter pigment phenotype, including red hair/fair skin (11), with poor tanning responses (12) and an increased risk for melanoma and other skin cancers (13,14).MC1R signaling can be inhibited by the product of the agouti locus, agouti signal protein (ASP in mice, ASIP in humans), which acts as an inverse agonist of the murine Mc1r (15,16). In mice, ASP is expressed in skin and testis and during embryogenesis. The spatiotemporal expression of ASP in skin is responsible for the agouti hair phenotype (a pheomelanic band against a dark eumelanic background) and for the pale coloration on the neck, breast, and ventral surface (17). A high degree of polymorphism in the promoter of t...