The interplay between Src family kinases and receptor tyrosine kinases.

Src family tyrosine kinases (SFKs) are involved in a diverse array of physiological processes, as highlighted in this review. An overview of how SFKs interact with, and participate in signaling from, receptor tyrosine kinases (RTKs) is discussed. And also, how SFKs are activated by RTKs, and how SFKs, in turn, can activate RTKs, as well as how SFKs can promote signaling from growth factor receptors in a number of ways including participation in signaling pathways required for DNA synthesis, control of receptor turnover, actin cytoskeleton rearrangements and motility, and survival are discussed.Peer reviewe

Platelet-derived growth factor stimulates Src-dependent mRNA stabilization of specific early genes in fibroblasts.

The Src family of protein-tyrosine kinases (SFKs) participates in a variety of signal transduction pathways, including promotion of cell growth, prevention of apoptosis, and regulation of cell interactions and motility. In particular, SFKs are required for the mitogenic response to platelet-derived growth factor (PDGF). However, it is not clear whether there is a discrete SFK-specific pathway leading to enhanced gene expression or whether SFKs act to generally enhance PDGF-stimulated gene expression. To examine this, we treated quiescent NIH3T3 cells with PDGF in the presence or absence of small molecule inhibitors of SFKs, phosphatidylinositol 3-kinase (PI3K), and MEK1/2. Global patterns of gene expression were analyzed by using Affymetrix Gene-Chip arrays, and data were validated by using reverse transcription-PCR and ribonuclease protection assay. We identified a discrete set of immediate early genes induced by PDGF and inhibited in the presence of the SFK-selective inhibitor SU6656. A subset of these SFK-dependent genes was induced by PDGF even in the presence of the MEK1/2 inhibitor U0126 or the PI3K inhibitor LY294002. By using ribonuclease protection assays and nuclear run-off assays, we further determined that PDGF did not stimulate the rate of transcription of these SFK-dependent immediate early genes but rather promoted mRNA stabilization. Our data suggest that PDGF regulates gene expression through an SFK-specific pathway that is distinct from the Ras-MAPK and PI3K pathways, and that SFKs signal gene expression by enhancing mRNA stability.Peer reviewe

Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.

International audienceRecent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/beta-catenin pathway through the phosphorylation of GSK3-beta. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/beta-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells

Hepatitis viruses and the MAPK pathway: is this a survival strategy?

The viruses that cause hepatitis comprise of at least five different agents, which share the ability to cause inflammation and necrosis of the liver. The disease spectrum is quite diverse and the outcome of infection by the different hepatitis viruses can be rationalized based on virus-host cell interactions. New insights into the molecular basis of viral hepatitis reveal that three of these agents - the hepatitis B, C and E viruses (HBV, HCV and HEV) modulate the mitogen-activated protein kinase (MAPK) signaling pathway. In this review we briefly describe the structural organization of the MAPK cascade and emphasize its importance as a central pathway in the signaling network. Selected mechanisms through which HBV, HCV and HEV proteins target various steps in the MAPK pathway are discussed and used to propose a pro-survival outcome for the host cell. In addition, we offer an insight into how the common theme of MAPK activation and its downstream effects may be used to rationalize the different outcomes of hepatitis B, C and E

How viruses Evade host responses ?

Humans have evolved a highly complex defence system to combat a wide variety of pathogens. Among the pathogens, developing a remedy for most of the viral infections still remains a great challenge as viruses evolve very rapidly as well as produce a variety of proteins. These features provide viruses with strategies to evade almost any hurdle imposed by the host defences to block their replication. It is important to understand the mechanisms of virus-host interactions, as this information can prove useful in symptomatic treatment of viral infections and aid in the design of antiviral vaccines. Further, since viruses rely almost entirely on the host cell machinery for their propagation, these studies educate us about our own cells and the basic mechanisms of gene expression and immunity

Editorial: The Role of the EMT Program in Regulating the Immune Response in Carcinoma

International audienceNo abstract availabl

Plasticity and Potency of Mammary Stem Cell Subsets During Mammary Gland Development

It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, in which the mammary stem cells (MaSC) lie at the apex with regenerative capacity as well as plasticity. Despite the fact that the majority of studies supported the existence of multipotent MaSCs giving rise to both basal and luminal lineages, others proposed lineage restricted unipotent MaSCs. Consistent with the notion, the latest research has suggested that although normal MaSC subsets mainly stay in a quiescent state, they differ in their reconstituting ability, spatial localization, and molecular and epigenetic signatures in response to physiological stimuli within the respective microenvironment during the stages of mammary gland development. In this review, we will focus on current research on the biology of normal mammary stem cells with an emphasis on properties of cellular plasticity, self-renewal and quiescence, as well as the role of the microenvironment in regulating these processes. This will include a discussion of normal breast stem cell heterogeneity, stem cell markers, and lineage tracing studies