The Ras/Raf/extracellular signal‐regulated kinase (ERK) signaling pathway plays a crucial role in almost all cell functions and therefore requires exquisite control of its spatiotemporal activity. Depending on the cell type and stimulus, ERK activity will mediate different antiproliferative events, such as apoptosis, autophagy and senescence in vitro and in vivo. ERK activity can promote either intrinsic or extrinsic apoptotic pathways by induction of mitochondrial cytochrome c release or caspase‐8 activation, permanent cell cycle arrest or autophagic vacuolization. These unusual effects require sustained ERK activity in specific subcellular compartments and could depend on the presence of reactive oxygen species. We will summarize the mechanisms involved in Ras/Raf/ERK antiproliferative functions.

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The mitogen-activated protein kinases (MAP (25) and that sustained activation of MAP kinase during G1 progression appears to be essential for triggering entry into the S phase ofthe cell cycle (25,26). Here, exploiting the use of either MAP kinase antisense or dominant negative alleles, we directly demonstrate that MAP kinase activation is essential for Go-arrested fibroblasts to enter the cell cycle. MATERIALS AND METHODSMaterials. Highly purified human a-thrombin (3200 NIH units/mg) and human recombinant basic fibroblast growth factor (FGF) were generous gifts of J.

The Ras/Raf/MEK/ERK signaling cascade that integrates an extreme variety of extracellular stimuli into key biological responses controlling cell proliferation, differentiation or death is one of the most studied intracellular pathways. Here we present some evidences that have been accumulated over the last 15 years proving the requirement of ERK in the control of cell proliferation. In this review we focus (i) on the spatio-temporal control of ERK signaling, (ii) on the key cellular components linking extracellular signals to the induction and activation of cell cycle events controlling G1 to S-phase transition and (iii) on the role of ERK in the growth factor-independent G2/M phase of the cell cycle. As ERK pathway is often co-activated with the PI3 kinase signaling, we highlight some of the key points of convergence leading to a full activation of mTOR via ERK and AKT synergies. Finally, ERK and AKT targets being constitutively activated in so many human cancers, we briefly touched the cure issue of using more specific drugs in rationally selected cancer patients.

Disruption of the endothelial barrier by tumour-derived secreted factors is a critical step in cancer cell extravasation and metastasis. Here, by comparative proteomic analysis of melanoma secretomes, we identify the matricellular protein SPARC as a novel tumour-derived vascular permeability factor. SPARC deficiency abrogates tumour-initiated permeability of lung capillaries and prevents extravasation, whereas SPARC overexpression enhances vascular leakiness, extravasation and lung metastasis. SPARC-induced paracellular permeability is dependent on the endothelial VCAM1 receptor and p38 MAPK signalling. Blocking VCAM1 impedes melanoma-induced endothelial permeability and extravasation. The clinical relevance of our findings is highlighted by high levels of SPARC detected in tumour from human pulmonary melanoma lesions. Our study establishes tumour-produced SPARC and VCAM1 as regulators of cancer extravasation, revealing a novel targetable interaction for prevention of metastasis.